rs200239095

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_001164507.2(NEB):c.20032C>T(p.Arg6678Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000407 in 1,597,844 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts 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. R6678H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 4 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.14

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 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011472553).

BP6

Variant 2-151549653-G-A is Benign according to our data. Variant chr2-151549653-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 331438.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.20032C>T	p.Arg6678Cys	missense_variant	Exon 130 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.20032C>T	p.Arg6678Cys	missense_variant	Exon 130 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.20032C>T	p.Arg6678Cys	missense_variant	Exon 130 of 182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 link	c.20032C>T	p.Arg6678Cys	missense_variant	Exon 130 of 182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000813

AC:

185

AN:

227490

AF XY:

0.000851

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000931

Gnomad ASJ exome

AF:

0.0150

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000315

Gnomad OTH exome

AF:

0.00123

GnomAD4 exome

AF:

0.000401

AC:

580

AN:

1445732

Hom.:

Cov.:

AF XY:

0.000427

AC XY:

306

AN XY:

717466

show subpopulations

African (AFR)

AF:

0.0000601

AC:

AN:

33302

American (AMR)

AF:

0.0000701

AC:

AN:

42770

Ashkenazi Jewish (ASJ)

AF:

0.0152

AC:

391

AN:

25796

East Asian (EAS)

AF:

0.000229

AC:

AN:

39222

South Asian (SAS)

AF:

0.0000240

AC:

AN:

83264

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52578

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.0000925

AC:

102

AN:

1103226

Other (OTH)

AF:

0.00117

AC:

AN:

59836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000467

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.00103

Hom.:

Bravo

AF:

0.000548

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000256

AC:

ESP6500EA

AF:

0.000719

AC:

ExAC

AF:

0.000571

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Uncertain:1Benign:2

Jan 24, 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:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Dec 26, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Aug 20, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEB: BP4, BS2 -

NEB-related disorder

Benign:1

May 10, 2023

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.073

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

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

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

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.011

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

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.4

L;.;.;.;L;.;.;.

PhyloP100

5.1

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.9

D;N;.;D;D;D;.;.

REVEL

Uncertain

0.30

Sift

Uncertain

0.0060

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

Sift4G

Uncertain

0.010

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

Polyphen

0.98

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

Vest4

0.35

MVP

0.66

MPC

0.36

ClinPred

0.14

GERP RS

6.2

Varity_R

0.14

gMVP

0.20

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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