rs148095660

Variant names:

• chr2-151562719-C-T
• rs148095660
• NM_001164507.2:c.18783G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.18783G>A is a synonymous (silent) variant (p.Gln6261=) that is not predicted by SpliceAI to impact splicing. However, it occurs at a nucleotide that is conserved as shown by the UCSC Genome Browser (BP4, BP7 not met). The highest population filtering allele frequency in gnomAD v4.1.0 is 0.02590 (2413/89448 alleles, 58 homozygotes) in the South Asian population, which is higher than the ClinGen Congenital Myopathies threshold (≥0.00559) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA203801/MONDO:0018958/146

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (60 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: 0.777

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 Benign. Variant got -8 ACMG points.

• BA1: 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.18783G>A	p.Gln6261Gln	synonymous_variant	Exon 120 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.18783G>A	p.Gln6261Gln	synonymous_variant	Exon 120 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.18783G>A	p.Gln6261Gln	synonymous_variant	Exon 120 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.18783G>A	p.Gln6261Gln	synonymous_variant	Exon 120 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 265 AN: 152138 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00400 AC: 959 AN: 239474 Hom.: 16 AF XY: 0.00503 AC XY: 651 AN XY: 129372

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.000240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00518

Gnomad SAS exome AF: 0.0269

Gnomad FIN exome AF: 0.000189

Gnomad NFE exome AF: 0.000332

Gnomad OTH exome AF: 0.00290

GnomAD4 exome AF: 0.00207 AC: 3005 AN: 1454398 Hom.: 60 Cov.: 31 AF XY: 0.00276 AC XY: 1998 AN XY: 722736

Gnomad4 AFR exome AF: 0.00135

Gnomad4 AMR exome AF: 0.000182

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00294

Gnomad4 SAS exome AF: 0.0268

Gnomad4 FIN exome AF: 0.000395

Gnomad4 NFE exome AF: 0.000325

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.00174 AC: 265 AN: 152254 Hom.: 2 Cov.: 31 AF XY: 0.00216 AC XY: 161 AN XY: 74432

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00328

Gnomad4 SAS AF: 0.0297

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000638 Hom.: 1

Bravo AF: 0.00117

Asia WGS AF: 0.0250 AC: 88 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Apr 15, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 16, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nemaline myopathy 2 Benign:3

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nemaline myopathy Benign:1

Aug 07, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.18783G>A is a synonymous (silent) variant (p.Gln6261=) that is not predicted by SpliceAI to impact splicing. However, it occurs at a nucleotide that is conserved as shown by the UCSC Genome Browser (BP4, BP7 not met). The highest population filtering allele frequency in gnomAD v4.1.0 is 0.02590 (2413/89448 alleles, 58 homozygotes) in the South Asian population, which is higher than the ClinGen Congenital Myopathies threshold (≥0.00559) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	7.7
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs148095660; hg19: chr2-152419233;