rs117048449

Variant names:

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.3412A>G(p.Asn1138Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00313 in 1,613,996 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 16 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 110 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.58

Publications

9 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=0.003719896).

BP6

Variant 2-151678031-T-C is Benign according to our data. Variant chr2-151678031-T-C is described in ClinVar as Benign. ClinVar VariationId is 129740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.3412A>G	p.Asn1138Asp	missense_variant	Exon 33 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.3412A>G	p.Asn1138Asp	missense_variant	Exon 33 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.3412A>G	p.Asn1138Asp	missense_variant	Exon 33 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.3412A>G	p.Asn1138Asp	missense_variant	Exon 33 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.3412A>G	p.Asn1138Asp	missense_variant	Exon 33 of 150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00423

AC:

643

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00805

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0691

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00782

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00880

AC:

2193

AN:

249156

AF XY:

0.00815

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.0137

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0769

Gnomad FIN exome

AF:

0.00691

Gnomad NFE exome

AF:

0.000691

Gnomad OTH exome

AF:

0.00578

GnomAD4 exome

AF:

0.00302

AC:

4408

AN:

1461702

Hom.:

110

Cov.:

AF XY:

0.00297

AC XY:

2157

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.0129

AC:

575

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0654

AC:

2597

AN:

39700

South Asian (SAS)

AF:

0.00213

AC:

184

AN:

86258

European-Finnish (FIN)

AF:

0.00794

AC:

424

AN:

53398

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000263

AC:

292

AN:

1111864

Other (OTH)

AF:

0.00543

AC:

328

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

249

498

748

997

1246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<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:

0.00422

AC:

642

AN:

152294

Hom.:

Cov.:

AF XY:

0.00471

AC XY:

351

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41556

American (AMR)

AF:

0.00804

AC:

123

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0687

AC:

356

AN:

5184

South Asian (SAS)

AF:

0.00311

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00782

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68028

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

130

163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00310

Hom.:

Bravo

AF:

0.00468

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000257

AC:

ESP6500EA

AF:

0.000483

AC:

ExAC

AF:

0.00815

AC:

985

Asia WGS

AF:

0.0240

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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. -

Feb 13, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 18, 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. -

not provided

Benign:3

Mar 26, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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.3412A>G (p.Asn1138Asp) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 982/120580 control chromosomes (26 homozygotes) from ExAC at a frequency of 0.008144, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this variant is likely a benign polymorphism. The variant is more common in East Asian sub-population with allele frequency of 7.57% (652/8602 chromosomes). In one case-control study, this variant did not confer increased risk for prostate cancer (Haiman_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Nemaline myopathy 2

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.034

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

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

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

MetaRNN

Benign

0.0037

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

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.1

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

PhyloP100

4.6

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.7

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

REVEL

Benign

0.12

Sift

Benign

0.20

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

Sift4G

Uncertain

0.037

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

Polyphen

0.95

.;.;.;.;P;.;.

Vest4

0.54

MVP

0.49

MPC

0.11

ClinPred

0.057

GERP RS

5.6

Varity_R

0.22

gMVP

0.38

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