2-151640012-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001164507.2(NEB):c.8734T>C(p.Ser2912Pro) variant causes a missense change. The variant allele was found at a frequency of 0.207 in 1,613,564 control chromosomes in the GnomAD database, including 49,168 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 11054 hom., cov: 32)

Exomes 𝑓: 0.20 ( 38114 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 5.43

Publications

33 publications found

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 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

NEB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.8599122E-5).

BP6

Variant 2-151640012-A-G is Benign according to our data. Variant chr2-151640012-A-G is described in ClinVar as Benign. ClinVar VariationId is 129761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.8734T>C	p.Ser2912Pro	missense_variant	Exon 62 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.8734T>C	p.Ser2912Pro	missense_variant	Exon 62 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.8734T>C	p.Ser2912Pro	missense_variant	Exon 62 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.8734T>C	p.Ser2912Pro	missense_variant	Exon 62 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.8734T>C	p.Ser2912Pro	missense_variant	Exon 62 of 150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.313

AC:

47545

AN:

151980

Hom.:

10994

Cov.:

show subpopulations

Gnomad AFR

AF:

0.629

Gnomad AMI

AF:

0.176

Gnomad AMR

AF:

0.189

Gnomad ASJ

AF:

0.258

Gnomad EAS

AF:

0.607

Gnomad SAS

AF:

0.336

Gnomad FIN

AF:

0.131

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.158

Gnomad OTH

AF:

0.289

GnomAD2 exomes

AF:

0.243

AC:

60525

AN:

249014

AF XY:

0.240

show subpopulations

Gnomad AFR exome

AF:

0.644

Gnomad AMR exome

AF:

0.138

Gnomad ASJ exome

AF:

0.247

Gnomad EAS exome

AF:

0.594

Gnomad FIN exome

AF:

0.140

Gnomad NFE exome

AF:

0.158

Gnomad OTH exome

AF:

0.216

GnomAD4 exome

AF:

0.196

AC:

286005

AN:

1461466

Hom.:

38114

Cov.:

AF XY:

0.198

AC XY:

144180

AN XY:

727032

show subpopulations

African (AFR)

AF:

0.648

AC:

21699

AN:

33474

American (AMR)

AF:

0.145

AC:

6507

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.248

AC:

6487

AN:

26136

East Asian (EAS)

AF:

0.622

AC:

24692

AN:

39694

South Asian (SAS)

AF:

0.333

AC:

28694

AN:

86228

European-Finnish (FIN)

AF:

0.142

AC:

7576

AN:

53390

Middle Eastern (MID)

AF:

0.225

AC:

1296

AN:

5768

European-Non Finnish (NFE)

AF:

0.157

AC:

174583

AN:

1111690

Other (OTH)

AF:

0.240

AC:

14471

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

11901

23802

35702

47603

59504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6780

13560

20340

27120

33900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.313

AC:

47659

AN:

152098

Hom.:

11054

Cov.:

AF XY:

0.310

AC XY:

23054

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.630

AC:

26123

AN:

41456

American (AMR)

AF:

0.189

AC:

2887

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.258

AC:

895

AN:

3466

East Asian (EAS)

AF:

0.607

AC:

3139

AN:

5168

South Asian (SAS)

AF:

0.335

AC:

1617

AN:

4824

European-Finnish (FIN)

AF:

0.131

AC:

1387

AN:

10578

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.158

AC:

10759

AN:

67996

Other (OTH)

AF:

0.298

AC:

629

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1356

2713

4069

5426

6782

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

438

876

1314

1752

2190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.218

Hom.:

18676

Bravo

AF:

0.331

TwinsUK

AF:

0.153

AC:

569

ALSPAC

AF:

0.159

AC:

612

ESP6500AA

AF:

0.598

AC:

2256

ESP6500EA

AF:

0.165

AC:

1358

ExAC

AF:

0.254

AC:

30680

Asia WGS

AF:

0.546

AC:

1897

AN:

3478

EpiCase

AF:

0.154

EpiControl

AF:

0.160

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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.Ser2912Pro in exon 62 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 60% (2256/3774) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs6713162). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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. -

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. -

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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.8734T>C (p.Ser2912Pro) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not working at the time of classification). This variant was found in 30671/120746 control chromosomes (5615 homozygotes) at a frequency of 0.2540126, which is approximately 72 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), evidence this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Mar 04, 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

0.031

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.59

DEOGEN2

Benign

0.0032

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

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.58

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

MetaRNN

Benign

0.000039

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

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-2.8

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

PhyloP100

5.4

PrimateAI

Uncertain

0.57

PROVEAN

Benign

2.9

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

REVEL

Benign

0.11

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0

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

Vest4

0.16

MPC

0.061

ClinPred

0.0072

GERP RS

5.5

Varity_R

0.20

gMVP

0.37

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over