2-151671058-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001164508.2(NEB):c.4471G>A(p.Val1491Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 1,613,714 control chromosomes in the GnomAD database, including 519,826 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.66 ( 38361 hom., cov: 32)

Exomes 𝑓: 0.80 ( 481465 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 3.39

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1006094E-6).

BP6

Variant 2-151671058-C-T is Benign according to our data. Variant chr2-151671058-C-T is described in ClinVar as [Benign]. Clinvar id is 95131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151671058-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.4471G>A	p.Val1491Met	missense_variant	Exon 38 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.4471G>A	p.Val1491Met	missense_variant	Exon 38 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.4471G>A	p.Val1491Met	missense_variant	Exon 38 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.4471G>A	p.Val1491Met	missense_variant	Exon 38 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.4471G>A	p.Val1491Met	missense_variant	Exon 38 of 150	5		ENSP00000386259.1	P20929-4
NEB	ENST00000484968.1 link	n.323G>A		non_coding_transcript_exon_variant	Exon 1 of 3	4

Frequencies

GnomAD3 genomes

AF:

0.665

AC:

101125

AN:

151990

Hom.:

38358

Cov.:

show subpopulations

Gnomad AFR

AF:

0.294

Gnomad AMI

AF:

0.823

Gnomad AMR

AF:

0.806

Gnomad ASJ

AF:

0.739

Gnomad EAS

AF:

0.393

Gnomad SAS

AF:

0.659

Gnomad FIN

AF:

0.868

Gnomad MID

AF:

0.778

Gnomad NFE

AF:

0.841

Gnomad OTH

AF:

0.701

GnomAD3 exomes

AF:

0.751

AC:

187196

AN:

249228

Hom.:

74188

AF XY:

0.755

AC XY:

102072

AN XY:

135198

show subpopulations

Gnomad AFR exome

AF:

0.277

Gnomad AMR exome

AF:

0.860

Gnomad ASJ exome

AF:

0.749

Gnomad EAS exome

AF:

0.410

Gnomad SAS exome

AF:

0.653

Gnomad FIN exome

AF:

0.860

Gnomad NFE exome

AF:

0.842

Gnomad OTH exome

AF:

0.783

GnomAD4 exome

AF:

0.802

AC:

1172173

AN:

1461606

Hom.:

481465

Cov.:

AF XY:

0.800

AC XY:

581351

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.275

Gnomad4 AMR exome

AF:

0.852

Gnomad4 ASJ exome

AF:

0.748

Gnomad4 EAS exome

AF:

0.379

Gnomad4 SAS exome

AF:

0.663

Gnomad4 FIN exome

AF:

0.858

Gnomad4 NFE exome

AF:

0.843

Gnomad4 OTH exome

AF:

0.756

GnomAD4 genome

AF:

0.665

AC:

101130

AN:

152108

Hom.:

38361

Cov.:

AF XY:

0.669

AC XY:

49722

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.294

Gnomad4 AMR

AF:

0.806

Gnomad4 ASJ

AF:

0.739

Gnomad4 EAS

AF:

0.393

Gnomad4 SAS

AF:

0.659

Gnomad4 FIN

AF:

0.868

Gnomad4 NFE

AF:

0.841

Gnomad4 OTH

AF:

0.692

Alfa

AF:

0.797

Hom.:

123828

Bravo

AF:

0.644

TwinsUK

AF:

0.847

AC:

3142

ALSPAC

AF:

0.842

AC:

3244

ESP6500AA

AF:

0.320

AC:

1356

ESP6500EA

AF:

0.833

AC:

7030

ExAC

AF:

0.737

AC:

89227

Asia WGS

AF:

0.451

AC:

1572

AN:

3478

EpiCase

AF:

0.846

EpiControl

AF:

0.839

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Apr 05, 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. -

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. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a RefSeq error. The reference base (c.4471G) is the minor allele. This a llele (G) has been identified in 17% (1414/8444) of European American chromosome s and 68% (2878/4234) of African American chromosomes by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs7426114) and thus meets criteria to be classified as benign. -

Nemaline myopathy 2

Benign:4

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 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. -

not provided

Benign:3

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.4471G>A (p.Val1491Met) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO not working, MutationTaster not captured due to low p-value). This variant was found in 89152/120710 control chromosomes (34995 homozygotes) at a frequency of 0.7385635, which is approximately 209 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), evidence that this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 07, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.034

.;.;T;.;T;.;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.80

T;T;T;T;T;.;.

MetaRNN

Benign

0.0000011

T;T;T;T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.3

M;M;.;M;M;M;M

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.1

N;N;.;N;N;.;.

REVEL

Benign

0.085

Sift

Benign

0.030

D;T;.;T;D;.;.

Sift4G

Uncertain

0.012

D;D;D;D;D;D;D

Polyphen

0.82

.;.;.;.;P;.;.

Vest4

0.54

MPC

0.22

ClinPred

0.019

GERP RS

5.4

Varity_R

0.15

gMVP

0.43

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over