Criteria Specification Registry

Criteria Specification (CSpec) Registry is intended to provide access to the Criteria Specifications used and applied by ClinGen Variant Curation Expert Panels and biocurators in the classification of variants.

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Criteria Specification

ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAG2 Version 1.0.0

Version : 1.0.0 Release Notes :

Additional variants requested were added.

Severe Combined Immunodeficiency Disease VCEP

Released

10/9/2023

11:41:21

Rules for RAG2

Gene: RAG2 (HGNC:9832) HGNC Name: recombination activating 2 Transcripts: NM_000536.4 Disease: recombinase activating gene 2 deficiency (MONDO:0000573) Mode of Inheritance: Autosomal recessive inheritance

Criteria & Strength Specifications
PVS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts. Stand Alone Very Strong Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with two specifications: Given that the RAG2 protein is encoded by a single exon (based on MANE Select transcript NM_000536.4) and nonsense-mediated decay is not predicted for nonsense or frameshift variants, PVS1 cannot be applied at the default strength to RAG2 variants (indicated by the red boxes in the Flowchart), except in the case of full gene deletion or removing/altering critical domain: the PHD domain and core domain (indicated by the purple in the Flowchart). PVS1 can be applied to variants not predicted to undergo nonsense-mediated decay when removing/altering the critical PHD domain (spanning amino acids 414-487) and core domain (amino acids 1-383) based on recommendations from Walker et al., preprint. Modification Type: General recommendation,Gene-specific Strong Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification: For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein, at least one pathogenic variant must be present downstream in order to apply PVS1_Strong. Modification Type: General recommendation,Gene-specific Moderate Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification: For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein, when at least one pathogenic variant is not present downstream, downgrade to PVS1_Moderate. Modification Type: General recommendation Supporting Instructions: See attached PVS1 flowchart. Not Applicable
PS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T. Applicable if the previously established variant is classified as pathogenic by SCID VCEP specifications for RAG2. Modification Type: Gene-specific Moderate It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T Applicable if the previously established variant is classified as likely pathogenic by SCID VCEP specifications for RAG2. Modification Type: Gene-specific,Strength Supporting Not Applicable
PS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. Stand Alone Very Strong Use ClinGen SVI recommendations for de novo criteria (see instructions below). Modification Type: General recommendation,Gene-specific Strong Use ClinGen SVI recommendations for de novo criteria (see instructions below). Modification Type: General recommendation,Gene-specific Moderate Use ClinGen SVI recommendations for de novo criteria (see instructions below). Modification Type: General recommendation,Gene-specific Supporting Use ClinGen SVI recommendations for de novo criteria (see instructions below). Modification Type: General recommendation,Gene-specific Instructions: The following guidelines should be used when determining the phenotypic consistency of each proband: “Phenotype highly specific for gene” proband must meet at least PP4_Moderate criteria; “Phenotype consistent with gene but not highly specific” proband must meet PP4 criteria; “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”: proband has been asserted to have a SCID phenotype but does not meet PP4 criteria; Reduce points per proband by half if the phase is unconfirmed. Not Applicable
PS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. Stand Alone Very Strong Strong PS3 may potentially be applied at the default strength level of strong for evidence from an animal model expressing the variant of interest and recapitulating the RAG2-SCID phenotype. Modification Type: Gene-specific Moderate Strength of evidence from cellular models/in vitro studies is dependent upon abnormal result in a V(D)J recombination assay: PS3_Moderate: <25% of wild-type activity in Tirosh et al., 2019 (PMID: 29772310) At least one previously observed proband with the expressed RAG2 variant meeting PP4 is required to apply PS3 at any strength. Modification Type: Gene-specific,Strength Supporting Strength of evidence from cellular models/in vitro studies is dependent upon abnormal result in a V(D)J recombination assay: PS3_Supporting: 25-60% of wild-type activity in Tirosh et al., 2019 (PMID: 29772310) OR Reduced activity compared to wild type in Couëdel et al., 2010 (PMID: 20234091) At least one previously observed proband with the expressed RAG2 variant meeting PP4 is required to apply PS3 at any strength. Modification Type: Gene-specific,Strength Not Applicable
PS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. Stand Alone Very Strong Strong Moderate Supporting Instructions: When the variant has been detected in multiple unrelated affected individuals (with at least one core feature of T lymphopenia, congenital alopecia, and nail dystrophy), evaluate each proband with the PP4 criteria (see below) and add points across all probands. Exclude the proband used to satisfy the PP4 criteria and cap each additional proband’s contribution at 2pt. Caveat: variant must be sufficiently rare (meet PM2 specification). Not Applicable
PM1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Stand Alone Very Strong Strong Moderate Strength is dependent upon the location of the variant within specific functional domains (PMID: 26996199): PM1_Moderate: missense variant located in the PHD domain (amino acids 414-487); Modification Type: Gene-specific Supporting Strength is dependent upon the location of the variant within specific functional domains (PMID: 26996199): PM1_Supporting: missense variant located in the core domain (amino acids 1-383); Modification Type: Gene-specific Not Applicable
PM2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Caveat: Population data for indels may be poorly called by next generation sequencing. Stand Alone Very Strong Strong Moderate Supporting gnomAD popmax filtering allele frequency <0.0000588 An additional requirement is that no homozygotes have been observed in gnomAD. Modification Type: Gene-specific Not Applicable
PM3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. Stand Alone Very Strong Use ClinGen SVI recommendations for in trans criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for RAG2. Modification Type: General recommendation Strong Use ClinGen SVI recommendations for in trans criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for RAG2. Modification Type: General recommendation Moderate Use ClinGen SVI recommendations for in trans criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for RAG2. Modification Type: General recommendation Supporting Use ClinGen SVI recommendations for in trans criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for RAG2. Modification Type: General recommendation Instructions: Caveat: All variants should be sufficiently rare (meet PM2 specification). The applicability of PM3 to suspected founder variants with allele frequencies exceeding the PM2 threshold will be evaluated on a case-by-case basis by the VCEP. Not Applicable
PM4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Stand Alone Very Strong Strong Moderate When applied to deletion variants, the deleted region must contain a known pathogenic or likely pathogenic variant that is not predicted/observed to alter splicing. Modification Type: Gene-specific Supporting When applied to deletion variants, the deleted region must contain a known VUS variant that is not predicted/observed to alter splicing. Modification Type: Gene-specific,Strength Not Applicable
PM5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong Moderate Applicable if a previously established variant is classified as pathogenic by SCID VCEP specifications for RAG2. Previously established variant must be classified by SCID VCEP specifications for RAG2. Modification Type: Gene-specific Supporting Applicable if a previously established variant is classified as likely pathogenic by SCID VCEP specifications for RAG2. Previously established variant must be classified by SCID VCEP specifications for RAG2. Modification Type: Gene-specific,Strength Not Applicable
PM6 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Assumed de novo, but without confirmation of paternity and maternity. Stand Alone Very Strong Strong Use ClinGen SVI recommendations for de novo criteria (see instructions below). Modification Type: General recommendation,Gene-specific Moderate Use ClinGen SVI recommendations for de novo criteria (see instructions below). Modification Type: General recommendation,Gene-specific Supporting Use ClinGen SVI recommendations for de novo criteria (see instructions below). Modification Type: General recommendation,Gene-specific Instructions: The following guidelines should be used when determining the phenotypic consistency of each proband: “Phenotype highly specific for gene” proband must meet at least PP4_Moderate criteria; “Phenotype consistent with gene but not highly specific” proband must meet PP4 criteria; “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”: proband has been asserted to have a SCID phenotype but does not meet PP4 criteria; Reduce points per proband by half if the phase is unconfirmed. Not Applicable
PP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data. Stand Alone Very Strong Strong Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations. Modification Type: General recommendation Moderate Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations. Modification Type: General recommendation Supporting Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations. Modification Type: General recommendation Instructions: Use ClinGen SVI recommendations for co-segregation criterion (PMID: 30311386) with the additional specification that unaffected individuals contributing to the calculated LOD score (Attached document: PP1 specifications) must be heterozygous carriers of one of the variants observed in the affected individuals (i.e. do not count wild-type/wild-type, individuals). Not Applicable
PP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Does not apply. The gnomAD v2.1.1 missense Z score for RAG2 (Z = 0.2) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in RAG2.
PP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting Only applicable to synonymous or intronic variants predicted to impact splicing by SpliceAI with a delta score greater than or equal to 0.2. Do not apply to missense variants. Modification Type: General recommendation Not Applicable
PP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. Stand Alone Very Strong Strong A patient score of ≥ 4 points¹. ¹CNV (Copy number variation) testing is required to consider PP4_Strong in order to certify that the variant in question is the causative for the phenotype and not one CNV event corrected by gene therapy and not identified previously (see instructions below). Modification Type: Disease-specific,Gene-specific Moderate A patient score of ≥2-<4 points (see instructions below). Modification Type: Disease-specific,Gene-specific Supporting A patient score of 1-<2 points (see instructions below). Modification Type: Disease-specific,Gene-specific Instructions: PP4 applicability and strength is determined by the total points accumulated by a single affected individual according to the list below: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met² (0.5pt) SCID gene panel or exome/genome sequencing conducted (only applicable if genetic testing did not provide an alternative genetic explanation for SCID/Leaky SCID/Omenn syndrome phenotype) (0.5pt) Family history of SCID (only applicable if SCID gene panel or exome/genome sequencing was conducted on proband and did not provide an alternative genetic explanation for phenotype) (0.5pt) Decreased presence of TCRVα7.2 in CD3+ T lymphocytes and/or mucosa-associated invariant T-cells demonstrated by flow cytometry (0.5pt) SCID phenotype corrected by RAG2 gene therapy WITHOUT CNV testing performed (1pt) SCID phenotype corrected by RAG2 gene therapy WITH CNV testing performed (4pt) T-B-NK+ lymphocyte subset profile* (See notes) (0.5pt) ²The diagnostic criteria should follow the PIDTC 2022 specification, summarized here. *Notes: 1) If NK cells are not noted or are present, criteria may still be applied if SCID gene panel or exome/genome sequencing has ruled out alternative causes; 2) If maternal T cells are present, the T lymphocyte profile is still considered to be T- (autologous T cells are absent). Find attached the PP4 table. Not Applicable
PP5
Original ACMG Summary Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BA1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Stand Alone gnomAD popmax filtering allele frequency >0.00872 Modification Type: Gene-specific Very Strong Strong Moderate Supporting Instructions: Maximum credible population allele frequency threshold determined using Whiffin/Ware calculator (https://www.cardiodb.org/allelefrequencyapp/) and the following parameters: Prevalence: 1:5,000 Allelic heterogeneity: 1 Genetic heterogeneity: 0.19 (based on the contribution of RAG2 variants to total SCID in the PIDTC 6901 cohort reported in Dvorak et al., 2019 (PMID: 30193840, Table 1): 19.2% rounded to 19%) Penetrance: 50% Not Applicable
BS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is greater than expected for disorder. Stand Alone Very Strong Strong gnomAD popmax filtering allele frequency >0.00195¹ ¹ Consider also bottleneck populations. Modification Type: Gene-specific Moderate Supporting Instructions: Maximum credible population allele frequency threshold determined using Whiffin/Ware calculator (https://www.cardiodb.org/allelefrequencyapp/) and the following parameters: Prevalence: 1:50,000 Allelic heterogeneity: 1 Genetic heterogeneity: 0.19 (based on the contribution of RAG2 variants to total SCID in the PIDTC 6901 cohort reported in Dvorak et al., 2019 (PMID: 30193840, Table 1): 19.2% rounded to 19%) Penetrance: 100% Not Applicable
BS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. Stand Alone Very Strong Strong Moderate Supporting Only to be used when the variant is observed in the homozygous state in a healthy adult. Modification Type: Strength Not Applicable Comments: Does not apply due to reduced penetrance.
BS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: There is not a well-established functional study which can rule out all damaging effects on protein function.
BS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Lack of segregation in affected members of a family. Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. Stand Alone Very Strong Strong Can be applied without additional specifications. Modification Type: General recommendation,None Moderate Supporting Not Applicable
BP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene for which primarily truncating variants are known to cause disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Does not apply.
BP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
BP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary In frame-deletions/insertions in a repetitive region without a known function. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Does not apply.
BP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
BP5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Variant found in a case with an alternate molecular basis for disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
BP6
Original ACMG Summary Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BP7 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Stand Alone Very Strong Strong Moderate Supporting Applicable to both synonymous variants and deep intronic variants affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions. The variant should be predicted not to impact splicing by at least two out of three in silico tools (freely available tools include GeneSplicer, MaxEntScan, NNSplice, SpliceAI, Splicing Sequences Finder (SSF), and varSEAK). Given the potential for poor conservation of genes related to T cell and B cell development among vertebrates, nucleotide conservation is not required in order to apply BP7. Modification Type: General recommendation Not Applicable

Rules for Combining Criteria

Pathogenic

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND ≥ 1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong, PP4_Strong)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND ≥ 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate) AND 1 Supporting (PS2_Supporting, PS3_Supporting, PM1_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND ≥ 2 Supporting (PS2_Supporting, PS3_Supporting, PM1_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

≥ 2 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong, PP4_Strong)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong, PP4_Strong) AND ≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong, PP4_Strong) AND 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PS2_Supporting, PS3_Supporting, PM1_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong, PP4_Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PS2_Supporting, PS3_Supporting, PM1_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

Likely Pathogenic

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND 1 Supporting (PS2_Supporting, PS3_Supporting, PM1_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong, PP4_Strong) AND ≥ 2 Supporting (PS2_Supporting, PS3_Supporting, PM1_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate)

2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PS2_Supporting, PS3_Supporting, PM1_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PS2_Supporting, PS3_Supporting, PM1_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

Benign

≥ 2 Strong (BS1, BS4)

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BS4)

2 Supporting (BS2_Supporting, BP7)

Files & Images

PVS1: Specified PVS1 flowchart

PM3: SVI recommendations for pm3 criterion

PP1: PP1 specifications

SCID VCEP PS3_BS3: Functional Evidence (RAG2)

PP4: RAG2

Additional RAG2 variants:

Pilot Phase: RAG2

PS2_PM6: SVI recommendations for de novo criteria