rs756363951

Positions:

• chr2-151650864-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3_Supporting PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.6937C>T (p.Arg2313Ter) variant in NEB is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 52/182 and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v.4.1.0 is 0.00001669 (1/59924) in Admixed American which meets the threshold (MAF≤0.0000559) to apply PM2_Supporting. The variant was found in one proband with nemaline myopathy in the literature with a second nonsense variant identified in trans (PM3_Supporting, PMID:25205138). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PM2_Supporting, PM3_Supporting (Congenital Myopathies VCEP specifications version 1; 09/16/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA1909950/MONDO:0018958/146

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 1.60

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.6937C>T	p.Arg2313*	stop_gained	53/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.6937C>T	p.Arg2313*	stop_gained	53/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.6937C>T	p.Arg2313*	stop_gained	53/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.6937C>T	p.Arg2313*	stop_gained	53/182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.6937C>T	p.Arg2313*	stop_gained	53/150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000807 AC: 2 AN: 247738 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134398

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000274 AC: 4 AN: 1459888 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Nemaline myopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 18, 2021	Variant summary: NEB c.6937C>T (p.Arg2313X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.1e-06 in 247738 control chromosomes (gnomAD). c.6937C>T has been reported in the literature in a family affected with Nemaline Myopathy 2 (Lehtokari_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen	Sep 16, 2024	The c.6937C>T (p.Arg2313Ter) variant in NEB is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 52/182 and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v.4.1.0 is 0.00001669 (1/59924) in Admixed American which meets the threshold (MAF≤0.0000559) to apply PM2_Supporting. The variant was found in one proband with nemaline myopathy in the literature with a second nonsense variant identified in trans (PM3_Supporting, PMID: 25205138). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PM2_Supporting, PM3_Supporting (Congenital Myopathies VCEP specifications version 1; 09/16/2024) -

Nemaline myopathy 2 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 19, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 27, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 552042). This premature translational stop signal has been observed in individual(s) with nemaline myopathy (PMID: 25205138). This variant is present in population databases (rs756363951, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg2313*) in the NEB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). -

NEB-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2023

The NEB c.6937C>T variant is predicted to result in premature protein termination (p.Arg2313*). This variant was reported in the compound heterozygous state in an individual with nemaline myopathy (Lehtokari et al 2014. PubMed ID: 25205138). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-152507378-G-A). Nonsense variants in NEB are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.91
GERP RS		4.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs756363951; hg19: chr2-152507378;