rs200269437

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001164507.2(NEB):c.24041T>C(p.Val8014Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000254 in 1,543,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V8014I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 3.67

Publications

2 publications found

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: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 was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11454207).

BP6

Variant 2-151499371-A-G is Benign according to our data. Variant chr2-151499371-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 506584.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.24041T>C	p.Val8014Ala	missense_variant	Exon 169 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.24041T>C	p.Val8014Ala	missense_variant	Exon 169 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 link	c.24041T>C	p.Val8014Ala	missense_variant	Exon 169 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7 link	c.24041T>C	p.Val8014Ala	missense_variant	Exon 169 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000154

AC:

AN:

155472

AF XY:

0.000134

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000369

Gnomad ASJ exome

AF:

0.000118

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000182

Gnomad OTH exome

AF:

0.000686

GnomAD4 exome

AF:

0.000264

AC:

367

AN:

1391726

Hom.:

Cov.:

AF XY:

0.000274

AC XY:

188

AN XY:

686854

show subpopulations

African (AFR)

AF:

0.0000956

AC:

AN:

31388

American (AMR)

AF:

0.000451

AC:

AN:

35490

Ashkenazi Jewish (ASJ)

AF:

0.0000399

AC:

AN:

25088

East Asian (EAS)

AF:

0.0000846

AC:

AN:

35468

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78962

European-Finnish (FIN)

AF:

0.0000206

AC:

AN:

48452

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.000307

AC:

330

AN:

1073446

Other (OTH)

AF:

0.000190

AC:

AN:

57758

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000164

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41440

American (AMR)

AF:

0.000131

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000192

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000298

Hom.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000568

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Dec 06, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jan 13, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nemaline myopathy 2

Uncertain:1Benign:1

Jan 10, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 30, 2019

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

NEB-related disorder

Uncertain:1

Mar 31, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The NEB c.24146T>C variant is predicted to result in the amino acid substitution p.Val8049Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.040% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6

Uncertain:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.010

.;T;.;.;.

Eigen

Benign

-0.0056

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.22

T;T;T;.;.

M_CAP

Benign

0.011

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-0.88

PhyloP100

3.7

PROVEAN

Benign

-0.85

N;.;N;.;.

REVEL

Benign

0.10

Sift

Benign

0.15

T;.;T;.;.

Sift4G

Benign

0.11

T;T;T;T;T

Vest4

0.28

MVP

0.50

MPC

0.059

ClinPred

0.060

GERP RS

6.1

gMVP

0.023

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over