rs10172023

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001164507.2(NEB):c.10809G>C(p.Trp3603Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,613,274 control chromosomes in the GnomAD database, including 80,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W3603R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.26 ( 5713 hom., cov: 32)

Exomes 𝑓: 0.32 ( 74739 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 3.22

Publications

21 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 Gene-Disease associations (from GenCC):

nemaline myopathy 2
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
childhood-onset nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
intermediate nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
typical nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
lethal multiple pterygium syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
severe congenital nemaline myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NEB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016649961).

BP6

Variant 2-151619514-C-G is Benign according to our data. Variant chr2-151619514-C-G is described in ClinVar as Benign. ClinVar VariationId is 95102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.10809G>C	p.Trp3603Cys	missense_variant	Exon 73 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.10809G>C	p.Trp3603Cys	missense_variant	Exon 73 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.10809G>C	p.Trp3603Cys	missense_variant	Exon 73 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.10809G>C	p.Trp3603Cys	missense_variant	Exon 73 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.10080G>C	p.Trp3360Cys	missense_variant	Exon 70 of 150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.262

AC:

39871

AN:

151940

Hom.:

5709

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.149

Gnomad AMR

AF:

0.264

Gnomad ASJ

AF:

0.225

Gnomad EAS

AF:

0.248

Gnomad SAS

AF:

0.216

Gnomad FIN

AF:

0.354

Gnomad MID

AF:

0.295

Gnomad NFE

AF:

0.330

Gnomad OTH

AF:

0.261

GnomAD2 exomes

AF:

0.292

AC:

72637

AN:

248552

AF XY:

0.290

show subpopulations

Gnomad AFR exome

AF:

0.139

Gnomad AMR exome

AF:

0.319

Gnomad ASJ exome

AF:

0.236

Gnomad EAS exome

AF:

0.263

Gnomad FIN exome

AF:

0.341

Gnomad NFE exome

AF:

0.326

Gnomad OTH exome

AF:

0.299

GnomAD4 exome

AF:

0.315

AC:

460833

AN:

1461216

Hom.:

74739

Cov.:

AF XY:

0.312

AC XY:

226923

AN XY:

726800

show subpopulations

African (AFR)

AF:

0.138

AC:

4605

AN:

33470

American (AMR)

AF:

0.313

AC:

13985

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.232

AC:

6063

AN:

26134

East Asian (EAS)

AF:

0.258

AC:

10251

AN:

39686

South Asian (SAS)

AF:

0.210

AC:

18107

AN:

86248

European-Finnish (FIN)

AF:

0.338

AC:

18072

AN:

53394

Middle Eastern (MID)

AF:

0.295

AC:

1702

AN:

5764

European-Non Finnish (NFE)

AF:

0.333

AC:

370215

AN:

1111458

Other (OTH)

AF:

0.295

AC:

17833

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

17421

34841

52262

69682

87103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11824

23648

35472

47296

59120

<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:

0.262

AC:

39883

AN:

152058

Hom.:

5713

Cov.:

AF XY:

0.263

AC XY:

19565

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.139

AC:

5786

AN:

41512

American (AMR)

AF:

0.265

AC:

4042

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.225

AC:

780

AN:

3464

East Asian (EAS)

AF:

0.248

AC:

1276

AN:

5154

South Asian (SAS)

AF:

0.217

AC:

1045

AN:

4824

European-Finnish (FIN)

AF:

0.354

AC:

3737

AN:

10564

Middle Eastern (MID)

AF:

0.297

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.330

AC:

22450

AN:

67960

Other (OTH)

AF:

0.258

AC:

546

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1479

2958

4438

5917

7396

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

416

832

1248

1664

2080

<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:

0.312

Hom.:

5653

Bravo

AF:

0.253

TwinsUK

AF:

0.340

AC:

1262

ALSPAC

AF:

0.338

AC:

1301

ESP6500AA

AF:

0.139

AC:

564

ESP6500EA

AF:

0.331

AC:

2784

ExAC

AF:

0.288

AC:

34864

Asia WGS

AF:

0.233

AC:

811

AN:

3478

EpiCase

AF:

0.313

EpiControl

AF:

0.312

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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.Trp3603Cys in exon 73 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 33% (2784/8400) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs10172023). -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

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:5

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 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

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Apr 24, 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.10809G>C (p.Trp3603Cys) variant involves the alteration of a non-conserved nucleotide and 3/3 in silico tools (SNPsandGo and Mutation Taster not captured here due to low reliability index and p-value, respectively) predict a damaging outcome. This variant was found in 34849/120540 control chromosomes (5272 homozygotes) at a frequency of 0.2891074, which is approximately 82 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Therefore, the variant of interest has been classified as Benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Pathogenic

0.94

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

.;.;T;.;D;.;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Benign

0.065

LIST_S2

Pathogenic

0.98

D;D;D;D;D;.;.

MetaRNN

Benign

0.0017

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

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.3

M;.;.;.;M;.;.

PhyloP100

3.2

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.2

D;D;.;D;D;.;.

REVEL

Uncertain

0.30

Sift

Uncertain

0.0060

D;D;.;D;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D

Polyphen

1.0

.;.;.;.;D;.;.

Vest4

0.68

MutPred

0.58

Loss of catalytic residue at W3360 (P = 0.0794);.;.;.;Loss of catalytic residue at W3360 (P = 0.0794);.;.;

MPC

0.42

ClinPred

0.016

GERP RS

5.6

Varity_R

0.59

gMVP

0.62

Mutation Taster

=99/1

polymorphism (auto)

(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