chr2-151490465-T-C

Variant names:

• chr2-151490465-T-C
• rs1061305
• NM_001164507.2:c.25204A>G

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.25204A>G​(p.Ile8402Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,606,238 control chromosomes in the GnomAD database, including 132,868 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.40 (12178 hom., cov: 31)
  • Exomes 𝑓: 0.40 (120690 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.715
• Publications: 30 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.4809113E-4).
• BP6: Variant 2-151490465-T-C is Benign according to our data. Variant chr2-151490465-T-C is described in ClinVar as Benign. ClinVar VariationId is 95126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.25204A>G	p.Ile8402Val	missense_variant	Exon 180 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.25204A>G	p.Ile8402Val	missense_variant	Exon 180 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.25204A>G	p.Ile8402Val	missense_variant	Exon 180 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.25204A>G	p.Ile8402Val	missense_variant	Exon 180 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60407 AN: 151876 Hom.: 12161 Cov.: 31

Gnomad AFR AF: 0.432

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.386

GnomAD2 exomes AF: 0.366 AC: 87104 AN: 237766 AF XY: 0.359

Gnomad AFR exome AF: 0.437

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.295

Gnomad EAS exome AF: 0.263

Gnomad FIN exome AF: 0.379

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.402 AC: 585038 AN: 1454244 Hom.: 120690 Cov.: 47 AF XY: 0.396 AC XY: 286115 AN XY: 722416

African (AFR) AF: 0.440 AC: 14664 AN: 33350

American (AMR) AF: 0.362 AC: 15893 AN: 43928

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 7600 AN: 25920

East Asian (EAS) AF: 0.280 AC: 11046 AN: 39444

South Asian (SAS) AF: 0.227 AC: 19193 AN: 84574

European-Finnish (FIN) AF: 0.383 AC: 20298 AN: 52954

Middle Eastern (MID) AF: 0.352 AC: 2024 AN: 5756

European-Non Finnish (NFE) AF: 0.426 AC: 471635 AN: 1108212

Other (OTH) AF: 0.377 AC: 22685 AN: 60106

GnomAD4 genome AF: 0.398 AC: 60463 AN: 151994 Hom.: 12178 Cov.: 31 AF XY: 0.391 AC XY: 29069 AN XY: 74304

African (AFR) AF: 0.433 AC: 17939 AN: 41462

American (AMR) AF: 0.356 AC: 5445 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 999 AN: 3470

East Asian (EAS) AF: 0.259 AC: 1335 AN: 5162

South Asian (SAS) AF: 0.225 AC: 1084 AN: 4824

European-Finnish (FIN) AF: 0.388 AC: 4093 AN: 10550

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.419 AC: 28437 AN: 67940

Other (OTH) AF: 0.382 AC: 804 AN: 2106

Alfa AF: 0.406 Hom.: 58355

Bravo AF: 0.401

TwinsUK AF: 0.430 AC: 1594

ALSPAC AF: 0.422 AC: 1627

ESP6500AA AF: 0.427 AC: 1744

ESP6500EA AF: 0.415 AC: 3495

ExAC AF: 0.364 AC: 43955

Asia WGS AF: 0.261 AC: 909 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Apr 05, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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.Ile8437Val in exon 181 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 41% (3495/8422) of European Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs1061305). -

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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. -

Nemaline myopathy 2 Benign:4

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

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. -

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

- -

not provided Benign:2

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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.25309A>G (p.Ile8437Val) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not functioning). This variant was found in 40099/96956 control chromosomes (7524 homozygotes) at a frequency of 0.4135794, which is approximately 117 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), evidence that this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this 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
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.7
DANN	Benign	0.94
DEOGEN2	Benign	0.0027	.;.;T;.;T;T;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.49	T;T;T;T;T;T;.;.
MetaRNN	Benign	0.00035	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N;.;.;.;N;.;.;.
PhyloP100		-0.71
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.25	N;N;.;N;N;N;.;.
REVEL	Benign	0.053
Sift	Benign	0.38	T;T;.;T;T;T;.;.
Sift4G	Benign	0.14	T;T;T;T;T;T;T;T
Polyphen		0.0010	.;.;.;.;B;.;.;.
Vest4		0.051
MPC		0.046
ClinPred		0.0015	T
GERP RS		0.40
Varity_R		0.052
gMVP		0.26
Mutation Taster		=98/2	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: rs1061305; hg19: chr2-152346979; COSMIC: COSV51445294; COSMIC: COSV51445294;