rs1061305

Positions:

chr2-151490465-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001164508.2(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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 12178 hom., cov: 31)

Exomes 𝑓: 0.40 ( 120690 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.715

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 links:

RIF1 (HGNC:):

RIF1 links:

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]

RIF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 95126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151490465-T-C is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.25204A>G	p.Ile8402Val	missense_variant	180/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.25204A>G	p.Ile8402Val	missense_variant	180/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.25204A>G	p.Ile8402Val	missense_variant	180/182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.25204A>G	p.Ile8402Val	missense_variant	180/182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.398

AC:

60407

AN:

151876

Hom.:

12161

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.366

AC:

87104

AN:

237766

Hom.:

16491

AF XY:

0.359

AC XY:

46145

AN XY:

128466

show subpopulations

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 SAS exome

AF:

0.231

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.:

AF XY:

0.396

AC XY:

286115

AN XY:

722416

show subpopulations

Gnomad4 AFR exome

AF:

0.440

Gnomad4 AMR exome

AF:

0.362

Gnomad4 ASJ exome

AF:

0.293

Gnomad4 EAS exome

AF:

0.280

Gnomad4 SAS exome

AF:

0.227

Gnomad4 FIN exome

AF:

0.383

Gnomad4 NFE exome

AF:

0.426

Gnomad4 OTH exome

AF:

0.377

GnomAD4 genome

AF:

0.398

AC:

60463

AN:

151994

Hom.:

12178

Cov.:

AF XY:

0.391

AC XY:

29069

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.433

Gnomad4 AMR

AF:

0.356

Gnomad4 ASJ

AF:

0.288

Gnomad4 EAS

AF:

0.259

Gnomad4 SAS

AF:

0.225

Gnomad4 FIN

AF:

0.388

Gnomad4 NFE

AF:

0.419

Gnomad4 OTH

AF:

0.382

Alfa

AF:

0.404

Hom.:

30883

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

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	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). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2017	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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.71

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

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

MutationAssessor

Benign

0.55

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

PrimateAI

Benign

0.27

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

GERP RS

0.40

Varity_R

0.052

gMVP

0.26

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over