Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_001164508.2(NEB):c.6076-1G>T

CA348802582

553493 (ClinVar)

Gene: NEB
Condition: nemaline myopathy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: c0faa268-cef1-4338-9232-2cc5e99b2022
Approved on: 2024-08-07
Published on: 2024-10-01

HGVS expressions

NM_001164508.2:c.6076-1G>T
NM_001164508.2(NEB):c.6076-1G>T
NC_000002.12:g.151658091C>A
CM000664.2:g.151658091C>A
NC_000002.11:g.152514605C>A
CM000664.1:g.152514605C>A
NC_000002.10:g.152222851C>A
NG_009382.2:g.81397G>T
ENST00000397345.8:c.6076-1G>T
ENST00000427231.7:c.6076-1G>T
ENST00000172853.14:c.6076-1G>T
ENST00000397345.7:c.6076-1G>T
ENST00000409198.5:c.6076-1G>T
ENST00000427231.6:c.6076-1G>T
ENST00000603639.5:c.6076-1G>T
ENST00000604864.5:c.6076-1G>T
ENST00000618972.4:c.6076-1G>T
NM_001164507.1:c.6076-1G>T
NM_001164508.1:c.6076-1G>T
NM_001271208.1:c.6076-1G>T
NM_004543.4:c.6076-1G>T
NM_001271208.2:c.6076-1G>T
NM_004543.5:c.6076-1G>T
NM_001164507.2:c.6076-1G>T
More

Likely Pathogenic

Met criteria codes 3
PVS1_Strong PM2_Supporting PM5
Not Met criteria codes 3
BS1 BA1 PM3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NEB Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Congenital Myopathies VCEP
The c.6076-1G>T variant in NEB occurs within the canonical splice acceptor site -1 of intron 47. It is predicted to cause skipping of biologically-relevant-exon 48/182, resulting in an in-frame deletion (removes amino acids 2026-2061) that is predicted to escape nonsense mediated decay (PVS1_Strong). The highest population minor allele frequency in gnomAD 4.1.0 is 0.00002698 (2/74116) in the African American population which meets the threshold to apply PM2_Supporting (MAF≤0.0000559). An additional pathogenic variant was identified in multiple affected probands at the same canonical splice acceptor site (c.6076-2A>C) (Invitae, SCV001204195.4) (PM5). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1_Strong, PM5, PM2_Supporting. (Congenital Myopathies VCEP specifications version 1; 8/7/2024)
Met criteria codes
PVS1_Strong
The c.6076-1G>T variant in NEB occurs within the canonical splice acceptor site -1 of intron 47. It is predicted to cause skipping of biologically-relevant-exon 48/182, resulting in an in-frame deletion (removes amino acids 2026-2061)
PM2_Supporting
The highest population minor allele frequency is 0.00002698 (2/74116) in the African American population (MAF meets PM2_P threshold)
PM5
An additional pathogenic variant was identified in multiple affected probands at the same canonical splice acceptor site, (c.6076-2A>C) (Invitae, SCV001204195.4)
Not Met criteria codes
BS1
The highest population minor allele frequency is 0.00002698 (2/74116) in the African American population
BA1
The highest population minor allele frequency is 0.00002698 (2/74116) in the African American population
PM3
Invitae identified this variant as heterozygous (no second NEB variant) in 2 unrelated adults undergoing carrier screening (and thus presumably clinically unaffected). An additional pathogenic variant was identified in multiple affected probands at the same canonical splice acceptor site, (c.6076-2A>C) (SCV001204195.4)
Curation History
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