chr2-151696713-T-C

Variant names:

• chr2-151696713-T-C
• rs1255744452
• NM_001164507.2:c.1493A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP4 PM2_Supporting PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_001164508.2 c.1493A>G (p.Asp498Gly) variant in NEB is a missense variant predicted to cause a substitution of aspartic acid by glycine at amino acid 498. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00005120 (1/19532) alleles) in East Asian population, which is lower than the ClinGen Congenital Myopathies VCEP threshold (≤0.0000559) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has previously been observed in probands who have had nemaline bodies on muscle biopsy (PMID:32403337; Invitae internal data SCV000659742.9) (PP4). The variant has previously been reported in trans with pathogenic variants or rare variants of uncertain significance in 4 probands with clinical features of congenital myopathy (PMID:33333461; Synnovis internal data SCV001468505.1; Invitae internal data SCV000659742.9) (PM3_Strong). In summary, this variant meets the criteria to be classified as likely pathogenic for Nemaline Myopathy for autosomal recessive inheritance based on the ACMG/AMP criteria applied as specified by the ClinGen Congenital Myopathy VCEP: (PM3_Strong, PP4, PM2_Supporting; ClinGen Congenital Myopathies VCEP Specifications version 1.0.0; 3/10/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA348825220/MONDO:0018958/146

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:5
• Conservation: PhyloP100: 4.17
• Publications: 0 publications found

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.1493A>G	p.Asp498Gly	missense_variant	Exon 17 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.1493A>G	p.Asp498Gly	missense_variant	Exon 17 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.1493A>G	p.Asp498Gly	missense_variant	Exon 17 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.1493A>G	p.Asp498Gly	missense_variant	Exon 17 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000489048.1	n.392A>G		non_coding_transcript_exon_variant	Exon 5 of 12	1
NEB	ENST00000409198.5	c.1493A>G	p.Asp498Gly	missense_variant	Exon 17 of 150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249190 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461530 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727046

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111758

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:5

Revision: reviewed by expert panel

Submissions by phenotype

Nemaline myopathy 2 Pathogenic:2 Uncertain:2

Jan 06, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Dec 22, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM3_Strong, PP3 -

Feb 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 498 of the NEB protein (p.Asp498Gly). This variant is present in population databases (no rsID available, gnomAD 0.005%). This missense change has been observed in individual(s) with nemaline myopathy (PMID: 32403337; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 533979). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nemaline myopathy Pathogenic:1 Uncertain:1

Mar 10, 2025

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_001164508.2 c.1493A>G (p.Asp498Gly) variant in NEB is a missense variant predicted to cause a substitution of aspartic acid by glycine at amino acid 498. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00005120 (1/19532) alleles) in East Asian population, which is lower than the ClinGen Congenital Myopathies VCEP threshold (≤0.0000559) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has previously been observed in probands who have had nemaline bodies on muscle biopsy (PMID:32403337; Invitae internal data SCV000659742.9) (PP4). The variant has previously been reported in trans with pathogenic variants or rare variants of uncertain significance in 4 probands with clinical features of congenital myopathy (PMID: 33333461; Synnovis internal data SCV001468505.1; Invitae internal data SCV000659742.9) (PM3_Strong). In summary, this variant meets the criteria to be classified as likely pathogenic for Nemaline Myopathy for autosomal recessive inheritance based on the ACMG/AMP criteria applied as specified by the ClinGen Congenital Myopathy VCEP: (PM3_Strong, PP4, PM2_Supporting; ClinGen Congenital Myopathies VCEP Specifications version 1.0.0; 3/10/2025). -

Mar 21, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Asp498Gly variant in NEB has been reported, in the compound heterozygous state, in one individual with nemaline myopathy (PMID: 32403337), and has been identified in 0.005% (3/59998) of Latino/Admixed chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1255744452). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 533979) and has been interpreted as a variant of uncertain significance by Baylor Genetics, Natera Inc., and GeneDx and as pathogenic by Invitae. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual heterozygous for this variant is highly specific for nemaline myopathy based on the presence of nemaline rods consistent with disease (PMID: 32403337). In summary, the clinical significance of the p.Asp498Gly variant is uncertain. ACMG/AMP Criteria applied: PP3, PP4, PM2_supporting, PM3_supporting (Richards 2015). -

Arthrogryposis multiplex congenita 6 Pathogenic:1

Sep 27, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Jun 20, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NEB c.1493A>G (p.Asp498Gly) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 4e-06 in 249190 control chromosomes. c.1493A>G has been observed in individuals affected with Nemaline Myopathy 2 (example: Gonzalez-Quered_2020, internal data). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33333461, 32403337). ClinVar contains an entry for this variant (Variation ID: 533979). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Uncertain:1

Feb 10, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32403337, 33333461) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	0.0039	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;.;T;.;T;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;.;.
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M;M;.;M;M;M;M
PhyloP100		4.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.2	N;N;.;N;N;.;.
REVEL	Benign	0.18
Sift	Uncertain	0.011	D;T;.;T;D;.;.
Sift4G	Uncertain	0.044	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.
Vest4		0.65
MutPred		0.29		Loss of ubiquitination at K501 (P = 0.0352);Loss of ubiquitination at K501 (P = 0.0352);Loss of ubiquitination at K501 (P = 0.0352);Loss of ubiquitination at K501 (P = 0.0352);Loss of ubiquitination at K501 (P = 0.0352);Loss of ubiquitination at K501 (P = 0.0352);Loss of ubiquitination at K501 (P = 0.0352);
MVP		0.59
MPC		0.17
ClinPred		0.95	D
GERP RS		5.9
Varity_R		0.35
gMVP		0.12
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1255744452; hg19: chr2-152553227;