chr2-151640012-A-G

Variant names:

• chr2-151640012-A-G
• rs6713162
• NM_001164507.2:c.8734T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.43
• Publications: 33 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 -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	c.8734T>C	p.Ser2912Pro	missense_variant	Exon 62 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	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	Appris	UniProt
NEB	ENST00000397345.8	c.8734T>C	p.Ser2912Pro	missense_variant	Exon 62 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.8734T>C	p.Ser2912Pro	missense_variant	Exon 62 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.8734T>C	p.Ser2912Pro	missense_variant	Exon 62 of 150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47545 AN: 151980 Hom.: 10994 Cov.: 32

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

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.: 33 AF XY: 0.198 AC XY: 144180 AN XY: 727032

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

GnomAD4 genome AF: 0.313 AC: 47659 AN: 152098 Hom.: 11054 Cov.: 32 AF XY: 0.310 AC XY: 23054 AN XY: 74360

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: 63 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10759 AN: 67996

Other (OTH) AF: 0.298 AC: 629 AN: 2114

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

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	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	22
DANN	Benign	0.59
DEOGEN2	Benign	0.0032	.;.;T;.;T;.;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.064	N
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	T
MutationAssessor	Benign	-2.8	N;N;.;N;N;N;N
PhyloP100		5.4
PrimateAI	Uncertain	0.57	T
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	T
GERP RS		5.5
Varity_R		0.20
gMVP		0.37
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: rs6713162; hg19: chr2-152496526; COSMIC: COSV50873704;