2-151717467-A-G

Variant names:

• chr2-151717467-A-G
• rs4611637
• NM_001164507.2:c.771T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001164507.2(NEB):​c.771T>C​(p.Ala257Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.788 in 1,613,292 control chromosomes in the GnomAD database, including 514,625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (38781 hom., cov: 32)
  • Exomes 𝑓: 0.80 (475844 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.311
• Publications: 21 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 2-151717467-A-G is Benign according to our data. Variant chr2-151717467-A-G is described in ClinVar as Benign. ClinVar VariationId is 95136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.311 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.771T>C	p.Ala257Ala	synonymous_variant	Exon 10 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.771T>C	p.Ala257Ala	synonymous_variant	Exon 10 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.771T>C	p.Ala257Ala	synonymous_variant	Exon 10 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.771T>C	p.Ala257Ala	synonymous_variant	Exon 10 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.771T>C	p.Ala257Ala	synonymous_variant	Exon 10 of 150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.681 AC: 103529 AN: 152040 Hom.: 38775 Cov.: 32

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.842

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.727

Gnomad EAS AF: 0.458

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.860

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.834

Gnomad OTH AF: 0.724

GnomAD2 exomes AF: 0.755 AC: 188045 AN: 249044 AF XY: 0.757

Gnomad AFR exome AF: 0.339

Gnomad AMR exome AF: 0.863

Gnomad ASJ exome AF: 0.737

Gnomad EAS exome AF: 0.475

Gnomad FIN exome AF: 0.852

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.788

GnomAD4 exome AF: 0.799 AC: 1167823 AN: 1461134 Hom.: 475844 Cov.: 48 AF XY: 0.796 AC XY: 578963 AN XY: 726886

African (AFR) AF: 0.345 AC: 11551 AN: 33468

American (AMR) AF: 0.856 AC: 38254 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.739 AC: 19301 AN: 26130

East Asian (EAS) AF: 0.439 AC: 17432 AN: 39684

South Asian (SAS) AF: 0.655 AC: 56514 AN: 86228

European-Finnish (FIN) AF: 0.850 AC: 45397 AN: 53388

Middle Eastern (MID) AF: 0.773 AC: 4461 AN: 5768

European-Non Finnish (NFE) AF: 0.836 AC: 929031 AN: 1111408

Other (OTH) AF: 0.760 AC: 45882 AN: 60348

GnomAD4 genome AF: 0.681 AC: 103547 AN: 152158 Hom.: 38781 Cov.: 32 AF XY: 0.684 AC XY: 50863 AN XY: 74386

African (AFR) AF: 0.356 AC: 14784 AN: 41470

American (AMR) AF: 0.811 AC: 12411 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.727 AC: 2524 AN: 3472

East Asian (EAS) AF: 0.458 AC: 2372 AN: 5178

South Asian (SAS) AF: 0.650 AC: 3139 AN: 4828

European-Finnish (FIN) AF: 0.860 AC: 9105 AN: 10586

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.834 AC: 56707 AN: 68010

Other (OTH) AF: 0.716 AC: 1512 AN: 2112

Alfa AF: 0.783 Hom.: 83053

Bravo AF: 0.665

Asia WGS AF: 0.498 AC: 1736 AN: 3478

EpiCase AF: 0.839

EpiControl AF: 0.834

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Nov 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala257Ala in exon 10 of NEB: This variant is not expected to have clinical sig nificance because it has been identified in 83% (6805/8228) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs4611637). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 11, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 05, 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:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 21, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The NEB c.771T>C (p.Ala257Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide, which 4/5 splice prediction tools predict no significant impact on normal splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 0.7437533 (89655/120544 (34969 homozygotes)), which indicates that the C allele is the major allele found in the general population. In addition, multiple clinical diagnostic laboratories classify the variant as Benign. Therefore, the variant of interest has been classified as Benign. -

Arthrogryposis multiplex congenita 6 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.33
DANN	Benign	0.54
PhyloP100		-0.31
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4611637; hg19: chr2-152573981; COSMIC: COSV50869840;