2-151674563-A-G

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.3901T>C(p.Tyr1301His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.861 in 1,612,734 control chromosomes in the GnomAD database, including 604,938 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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 0.81 ( 50716 hom., cov: 32)

Exomes 𝑓: 0.87 ( 554222 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.86

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=6.914382E-7).

BP6

Variant 2-151674563-A-G is Benign according to our data. Variant chr2-151674563-A-G is described in ClinVar as [Benign]. Clinvar id is 167336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.3901T>C	p.Tyr1301His	missense_variant	Exon 36 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.3901T>C	p.Tyr1301His	missense_variant	Exon 36 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.3901T>C	p.Tyr1301His	missense_variant	Exon 36 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.3901T>C	p.Tyr1301His	missense_variant	Exon 36 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.3901T>C	p.Tyr1301His	missense_variant	Exon 36 of 150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.808

AC:

122753

AN:

152010

Hom.:

50699

Cov.:

show subpopulations

Gnomad AFR

AF:

0.646

Gnomad AMI

AF:

0.852

Gnomad AMR

AF:

0.885

Gnomad ASJ

AF:

0.846

Gnomad EAS

AF:

0.575

Gnomad SAS

AF:

0.721

Gnomad FIN

AF:

0.889

Gnomad MID

AF:

0.889

Gnomad NFE

AF:

0.896

Gnomad OTH

AF:

0.831

GnomAD3 exomes

AF:

0.834

AC:

207597

AN:

249066

Hom.:

87982

AF XY:

0.832

AC XY:

112410

AN XY:

135112

show subpopulations

Gnomad AFR exome

AF:

0.640

Gnomad AMR exome

AF:

0.913

Gnomad ASJ exome

AF:

0.839

Gnomad EAS exome

AF:

0.595

Gnomad SAS exome

AF:

0.715

Gnomad FIN exome

AF:

0.882

Gnomad NFE exome

AF:

0.895

Gnomad OTH exome

AF:

0.853

GnomAD4 exome

AF:

0.867

AC:

1266546

AN:

1460606

Hom.:

554222

Cov.:

AF XY:

0.864

AC XY:

627693

AN XY:

726652

show subpopulations

Gnomad4 AFR exome

AF:

0.637

Gnomad4 AMR exome

AF:

0.909

Gnomad4 ASJ exome

AF:

0.843

Gnomad4 EAS exome

AF:

0.550

Gnomad4 SAS exome

AF:

0.724

Gnomad4 FIN exome

AF:

0.883

Gnomad4 NFE exome

AF:

0.896

Gnomad4 OTH exome

AF:

0.843

GnomAD4 genome

AF:

0.807

AC:

122809

AN:

152128

Hom.:

50716

Cov.:

AF XY:

0.807

AC XY:

60004

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.646

Gnomad4 AMR

AF:

0.885

Gnomad4 ASJ

AF:

0.846

Gnomad4 EAS

AF:

0.575

Gnomad4 SAS

AF:

0.721

Gnomad4 FIN

AF:

0.889

Gnomad4 NFE

AF:

0.896

Gnomad4 OTH

AF:

0.822

Alfa

AF:

0.872

Hom.:

119874

Bravo

AF:

0.801

TwinsUK

AF:

0.904

AC:

3352

ALSPAC

AF:

0.897

AC:

3456

ESP6500AA

AF:

0.660

AC:

2596

ESP6500EA

AF:

0.892

AC:

7412

ExAC

AF:

0.826

AC:

99831

Asia WGS

AF:

0.615

AC:

2142

AN:

3478

EpiCase

AF:

0.902

EpiControl

AF:

0.896

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Benign:3

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

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.3901T) is the minor allele. This a llele (T) has been identified in 11% (894/8306) of European American chromosomes and 34% (1336/3932) of African American chromosomes by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS/; dbSNP rs6711382) and thus meets c riteria to be classified as benign. -

Apr 05, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

0.040

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0019

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

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.0090

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

MetaRNN

Benign

6.9e-7

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

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.4

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

PrimateAI

Uncertain

0.58

PROVEAN

Benign

1.9

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

REVEL

Benign

0.11

Sift

Benign

0.46

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

Sift4G

Benign

0.65

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

Polyphen

0.0

.;.;.;.;B;.;.

Vest4

0.13

MPC

0.063

ClinPred

0.0057

GERP RS

5.5

Varity_R

0.032

gMVP

0.16

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