Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001164508.2(NEB):c.22590+2T>C

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA1906606

451052 (ClinVar)

Gene: NEB

Condition: nemaline myopathy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4d9de08c-55d1-4618-8434-bf3c179cac6d

Approved on: 2025-06-16

Published on: 2025-06-24

HGVS expressions

NM_001164508.2:c.22590+2T>C

NM_001164508.2(NEB):c.22590+2T>C

NC_000002.12:g.151519656A>G

CM000664.2:g.151519656A>G

NC_000002.11:g.152376170A>G

CM000664.1:g.152376170A>G

NC_000002.10:g.152084416A>G

NG_009382.2:g.219832T>C

ENST00000434685.6:c.2033+2T>C

ENST00000688161.1:n.380+2T>C

ENST00000690043.1:c.5441+2T>C

ENST00000693000.1:n.1615+2T>C

ENST00000693286.1:c.1388+2T>C

ENST00000397345.8:c.22590+2T>C

ENST00000427231.7:c.22590+2T>C

ENST00000172853.14:c.17487+2T>C

ENST00000397345.7:c.22590+2T>C

ENST00000409198.5:c.17487+2T>C

ENST00000413693.5:c.6780+2T>C

ENST00000427231.6:c.22590+2T>C

ENST00000434685.5:c.458+2T>C

ENST00000483418.1:n.328+2T>C

ENST00000603639.5:c.22590+2T>C

ENST00000604864.5:c.22590+2T>C

ENST00000618972.4:c.22695+2T>C

NM_001164507.1:c.22590+2T>C

NM_001164508.1:c.22590+2T>C

NM_001271208.1:c.22695+2T>C

NM_004543.4:c.17487+2T>C

NM_001271208.2:c.22695+2T>C

NM_004543.5:c.17487+2T>C

NM_001164507.2:c.22590+2T>C

Uncertain Significance

BS1 PVS1_Strong

PM3

Evidence Links 0

Expert Panel

Congenital Myopathies VCEP

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 NM_001164508.2:c.22590+2T>C variant in NEB occurs within the canonical splice donor site (+2) of intron 154. It is predicted to cause skipping of biologically-relevant-exon 154/182, resulting in an in-frame deletion (removes amino acids V7494-E7530). As per ClinGen Congenital Myopathies VCEP specifications, in-frame exon skipping of the NEB gene is an established disease mechanism in autosomal recessive nemaline myopathy (PVS1_Strong). The highest population minor allele frequency in gnomAD v4.1 is 0.0004030 (469/1163744 alleles) in European (non-Finnish) population, which is higher than the ClinGen Congenital Myopathies threshold ≥0.000237 for BS1 and therefore meets this criterion (BS1). Although this variant has been seen in the general population in a heterozygous state, with no homozygous observations, its frequency is not high enough to rule out a pathogenic role. This variant has been observed in individuals with congenital myopathies in a heterozygous state without a second variant. Therefore, no codes were applied (Internal data: GeneDx SCV000619698.7, CeGaT Center for Human Genetics Tuebingen SCV001152434.31, Fulgent Genetics SCV005650398.1). In summary, due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies: PVS1_Strong, BS1. (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 06/16/2025).

BS1

The highest population minor allele frequency in gnomAD v4.1 is 0.0004030 (469/1163744 alleles) in European (non-Finnish) population, which is higher than the ClinGen Congenital Myopathies threshold ≥0.000237 for BS1 and therefore meets this criterion (BS1). Although this variant has been seen in the general population in a heterozygous state, with no homozygous observations, its frequency is not high enough to rule out a pathogenic role.

PVS1_Strong

PM3

This variant has been observed in individuals with congenital myopathies in a heterozygous state without a second variant. Therefore, no codes were applied. (Internal data: GeneDx SCV000619698.7, CeGaT Center for Human Genetics Tuebingen SCV001152434.31, Fulgent Genetics SCV005650398.1).

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.