rs35740585

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001164508.2(NEB):c.11729A>G(p.Asp3910Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,613,868 control chromosomes in the GnomAD database, including 360 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 32 hom., cov: 32)

Exomes 𝑓: 0.020 ( 328 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.62

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004578173).

BP6

Variant 2-151612262-T-C is Benign according to our data. Variant chr2-151612262-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 129707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151612262-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.014 (2125/152296) while in subpopulation NFE AF= 0.0217 (1477/68026). AF 95% confidence interval is 0.0208. There are 32 homozygotes in gnomad4. There are 1035 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.11729A>G	p.Asp3910Gly	missense_variant	Exon 78 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.11729A>G	p.Asp3910Gly	missense_variant	Exon 78 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.11729A>G	p.Asp3910Gly	missense_variant	Exon 78 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.11729A>G	p.Asp3910Gly	missense_variant	Exon 78 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.11000A>G	p.Asp3667Gly	missense_variant	Exon 75 of 150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.0140

AC:

2126

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00420

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00746

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0282

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0217

Gnomad OTH

AF:

0.0138

GnomAD3 exomes

AF:

0.0147

AC:

3658

AN:

248950

Hom.:

AF XY:

0.0144

AC XY:

1939

AN XY:

135046

show subpopulations

Gnomad AFR exome

AF:

0.00342

Gnomad AMR exome

AF:

0.00678

Gnomad ASJ exome

AF:

0.00358

Gnomad EAS exome

AF:

0.000112

Gnomad SAS exome

AF:

0.00490

Gnomad FIN exome

AF:

0.0266

Gnomad NFE exome

AF:

0.0223

Gnomad OTH exome

AF:

0.0164

GnomAD4 exome

AF:

0.0196

AC:

28596

AN:

1461572

Hom.:

328

Cov.:

AF XY:

0.0190

AC XY:

13824

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.00379

Gnomad4 AMR exome

AF:

0.00631

Gnomad4 ASJ exome

AF:

0.00425

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00489

Gnomad4 FIN exome

AF:

0.0285

Gnomad4 NFE exome

AF:

0.0226

Gnomad4 OTH exome

AF:

0.0160

GnomAD4 genome

AF:

0.0140

AC:

2125

AN:

152296

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1035

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00419

Gnomad4 AMR

AF:

0.00745

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.0282

Gnomad4 NFE

AF:

0.0217

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0193

Hom.:

Bravo

AF:

0.0122

TwinsUK

AF:

0.0232

AC:

ALSPAC

AF:

0.0239

AC:

ESP6500AA

AF:

0.00430

AC:

ESP6500EA

AF:

0.0229

AC:

192

ExAC

AF:

0.0149

AC:

1799

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0192

EpiControl

AF:

0.0187

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 29, 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. -

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 05, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nemaline myopathy 2

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2018

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.078

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

Eigen

Benign

0.048

Eigen_PC

Benign

0.086

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.83

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

MetaRNN

Benign

0.0046

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

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

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

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.0

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

REVEL

Benign

0.14

Sift

Uncertain

0.029

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

Sift4G

Uncertain

0.0060

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

Polyphen

0.49

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

Vest4

0.38

MPC

0.094

ClinPred

0.020

GERP RS

3.1

Varity_R

0.11

gMVP

0.41

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over