rs201714437

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The c.25463A>G (p.Lys8488Arg) variant in NEB is a missense variant predicted to cause substitution of lysine by arginine at amino acid 8488. The highest population filtering allele frequency in gnomAD v4.1.0 is 0.0009555 (1161/1179882 alleles) in the European (non-Finnish) population, which is higher than the ClinGen Congenital Myopathies threshold (MAF≥0.000237) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.174, which is neither above nor below the thresholds predicting a damaging or benign impact on NEB function. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BS1. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA1905697/MONDO:0018958/146

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00078 ( 0 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:9B:2

Conservation

PhyloP100: 1.48

Publications

3 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 -4 ACMG points.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.25463A>G	p.Lys8488Arg	missense_variant	Exon 182 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.25463A>G	p.Lys8488Arg	missense_variant	Exon 182 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.25463A>G	p.Lys8488Arg	missense_variant	Exon 182 of 182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 link	c.25463A>G	p.Lys8488Arg	missense_variant	Exon 182 of 182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000313

AC:

AN:

248884

AF XY:

0.000296

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000674

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000783

AC:

1144

AN:

1461664

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

547

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00100

AC:

1117

AN:

1111842

Other (OTH)

AF:

0.000348

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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:

0.000322

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41460

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000647

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.000707

Hom.:

Bravo

AF:

0.000359

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000497

AC:

ESP6500EA

AF:

0.000714

AC:

ExAC

AF:

0.000281

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.000711

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:9Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:3

May 31, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Nov 15, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 13, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nemaline myopathy 2

Uncertain:2Benign:1

Aug 30, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Feb 19, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:2

Jul 21, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 11, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NEB c.25568A>G (p.Lys8523Arg) results in a conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 120734 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NEB causing Nemaline Myopathy 2 (0.00028 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.25568A>G in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.19895A>G (p.K6632R) alteration is located in exon 150 (coding exon 148) of the NEB gene. This alteration results from a A to G substitution at nucleotide position 19895, causing the lysine (K) at amino acid position 6632 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

NEB-related disorder

Uncertain:1

Feb 14, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NEB c.25568A>G variant is predicted to result in the amino acid substitution p.Lys8523Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.064% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-152342389-T-C). In ClinVar, this variant has been classified as uncertain and likely benign by several clinical labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/435961/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Nemaline myopathy

Benign:1

Aug 07, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.25463A>G (p.Lys8488Arg) variant in NEB is a missense variant predicted to cause substitution of lysine by arginine at amino acid 8488. The highest population filtering allele frequency in gnomAD v4.1.0 is 0.0009555 (1161/1179882 alleles) in the European (non-Finnish) population, which is higher than the ClinGen Congenital Myopathies threshold (MAF≥0.000237) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.174, which is neither above nor below the thresholds predicting a damaging or benign impact on NEB function. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BS1. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.026

.;.;T;.;T;T;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.096

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.71

T;T;T;T;T;T;.;.

M_CAP

Benign

0.021

MetaRNN

Benign

0.11

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.17

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

PhyloP100

1.5

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.2

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

REVEL

Benign

0.17

Sift

Benign

0.28

T;T;.;T;T;T;.;.

Sift4G

Benign

0.19

T;T;T;T;T;T;T;T

Polyphen

0.0060

.;.;.;.;B;.;.;.

Vest4

0.096

MVP

0.48

MPC

0.047

ClinPred

0.045

GERP RS

2.9

Varity_R

0.091

gMVP

0.24

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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