rs13031275

Variant names:

• chr2-151489980-A-C
• rs13031275
• NM_001164507.2:c.25395T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-151489980-A-C
• chr2-151489980-A-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001164507.2(NEB):​c.25395T>G​(p.Ser8465Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0544 in 1,590,030 control chromosomes in the GnomAD database, including 2,772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (154 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2618 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.804
• Publications: 9 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]

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.04).
• BP6: Variant 2-151489980-A-C is Benign according to our data. Variant chr2-151489980-A-C is described in ClinVar as Benign. ClinVar VariationId is 129735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.804 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.25395T>G	p.Ser8465Ser	synonymous_variant	Exon 181 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.25395T>G	p.Ser8465Ser	synonymous_variant	Exon 181 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.25395T>G	p.Ser8465Ser	synonymous_variant	Exon 181 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.25395T>G	p.Ser8465Ser	synonymous_variant	Exon 181 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.0379 AC: 5775 AN: 152176 Hom.: 154 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0287

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0607

Gnomad OTH AF: 0.0373

GnomAD2 exomes AF: 0.0418 AC: 10392 AN: 248880 AF XY: 0.0425

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.0217

Gnomad ASJ exome AF: 0.0451

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0311

Gnomad NFE exome AF: 0.0657

Gnomad OTH exome AF: 0.0437

GnomAD4 exome AF: 0.0561 AC: 80722 AN: 1437736 Hom.: 2618 Cov.: 29 AF XY: 0.0554 AC XY: 39726 AN XY: 716786

African (AFR) AF: 0.00966 AC: 318 AN: 32914

American (AMR) AF: 0.0232 AC: 1038 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 1191 AN: 26016

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39576

South Asian (SAS) AF: 0.0219 AC: 1874 AN: 85754

European-Finnish (FIN) AF: 0.0336 AC: 1796 AN: 53378

Middle Eastern (MID) AF: 0.0353 AC: 202 AN: 5724

European-Non Finnish (NFE) AF: 0.0657 AC: 71583 AN: 1090104

Other (OTH) AF: 0.0456 AC: 2717 AN: 59582

GnomAD4 genome AF: 0.0379 AC: 5772 AN: 152294 Hom.: 154 Cov.: 32 AF XY: 0.0352 AC XY: 2621 AN XY: 74474

African (AFR) AF: 0.0119 AC: 495 AN: 41566

American (AMR) AF: 0.0267 AC: 409 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 171 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4828

European-Finnish (FIN) AF: 0.0287 AC: 305 AN: 10610

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0607 AC: 4131 AN: 68020

Other (OTH) AF: 0.0369 AC: 78 AN: 2114

Alfa AF: 0.0566 Hom.: 891

Bravo AF: 0.0375

Asia WGS AF: 0.00953 AC: 34 AN: 3478

EpiCase AF: 0.0599

EpiControl AF: 0.0622

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

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. -

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.Ser8500Ser in exon 182 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 6.5% (530/8194) of European Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs13031275). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 26, 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:3

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.9
DANN	Benign	0.75
PhyloP100		-0.80
Mutation Taster		=96/4	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: rs13031275; hg19: chr2-152346494;