rs4664475

Variant names:

• chr2-151531039-T-C
• rs4664475
• NM_001164507.2:c.21585A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-151531039-T-C
• chr2-151531039-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001164507.2(NEB):​c.21585A>G​(p.Thr7195Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 1,611,460 control chromosomes in the GnomAD database, including 297,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24444 hom., cov: 31)
  • Exomes 𝑓: 0.61 (273354 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -3.29
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-151531039-T-C is Benign according to our data. Variant chr2-151531039-T-C is described in ClinVar as Benign. ClinVar VariationId is 95114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.21585A>G	p.Thr7195Thr	synonymous_variant	Exon 145 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.21585A>G	p.Thr7195Thr	synonymous_variant	Exon 145 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.21585A>G	p.Thr7195Thr	synonymous_variant	Exon 145 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.21585A>G	p.Thr7195Thr	synonymous_variant	Exon 145 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.555 AC: 84284 AN: 151820 Hom.: 24422 Cov.: 31

Gnomad AFR AF: 0.389

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.681

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.565

GnomAD2 exomes AF: 0.589 AC: 145970 AN: 247906 AF XY: 0.579

Gnomad AFR exome AF: 0.389

Gnomad AMR exome AF: 0.724

Gnomad ASJ exome AF: 0.523

Gnomad EAS exome AF: 0.578

Gnomad FIN exome AF: 0.639

Gnomad NFE exome AF: 0.620

Gnomad OTH exome AF: 0.610

GnomAD4 exome AF: 0.608 AC: 886922 AN: 1459522 Hom.: 273354 Cov.: 39 AF XY: 0.601 AC XY: 436676 AN XY: 726030

African (AFR) AF: 0.387 AC: 12933 AN: 33448

American (AMR) AF: 0.716 AC: 31948 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 13575 AN: 26116

East Asian (EAS) AF: 0.626 AC: 24832 AN: 39648

South Asian (SAS) AF: 0.410 AC: 35327 AN: 86088

European-Finnish (FIN) AF: 0.641 AC: 34202 AN: 53370

Middle Eastern (MID) AF: 0.602 AC: 3474 AN: 5766

European-Non Finnish (NFE) AF: 0.626 AC: 695049 AN: 1110194

Other (OTH) AF: 0.590 AC: 35582 AN: 60272

GnomAD4 genome AF: 0.555 AC: 84339 AN: 151938 Hom.: 24444 Cov.: 31 AF XY: 0.557 AC XY: 41374 AN XY: 74264

African (AFR) AF: 0.390 AC: 16118 AN: 41378

American (AMR) AF: 0.682 AC: 10407 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1770 AN: 3472

East Asian (EAS) AF: 0.582 AC: 3014 AN: 5178

South Asian (SAS) AF: 0.404 AC: 1942 AN: 4810

European-Finnish (FIN) AF: 0.644 AC: 6795 AN: 10556

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.625 AC: 42462 AN: 67966

Other (OTH) AF: 0.558 AC: 1178 AN: 2110

Alfa AF: 0.600 Hom.: 42917

Bravo AF: 0.556

Asia WGS AF: 0.451 AC: 1572 AN: 3478

EpiCase AF: 0.602

EpiControl AF: 0.612

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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.21690A) is the minor allele. This allele (A) has been identified in 38% (3158/8354) of European American chromosom es and 59% (2374/4046) of African American chromosomes by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs4664475) and thus meets criteria to be classified as benign. -

-

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 03, 2017

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. -

Apr 05, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nemaline myopathy 2 Benign:4

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

- -

Jan 12, 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 28, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.21690A>G (p.Thr7230Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 69172/118646 control chromosomes (20606 homozygotes) at a frequency of 0.5830116, which is approximately 165 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), evidence that this variant is a benign polymorphism. Multiple clinical diagnostic laboratories cite the variant as "benign." Taken together, this variant is classified as benign. -

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
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.094
DANN	Benign	0.53
PhyloP100		-3.3
Mutation Taster		=89/11	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: rs4664475; hg19: chr2-152387553; COSMIC: COSV51424628; COSMIC: COSV51424628;