rs117048449

Positions:

chr2-151678031-T-C

Variant summary

Our verdict is Benign. Variant got -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

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=0.003719896).

BP6

Variant 2-151678031-T-C is Benign according to our data. Variant chr2-151678031-T-C is described in ClinVar as [Benign]. Clinvar id is 129740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151678031-T-C is described in Lovd as [Likely_benign].

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/exons	MANE	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.3412A>G	p.Asn1138Asp	missense_variant	33/182	ENST00000427231.7
NEB	NM_001164508.2 linkuse as main transcript	c.3412A>G	p.Asn1138Asp	missense_variant	33/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.3412A>G	p.Asn1138Asp	missense_variant	33/182	5	NM_001164508.2	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.3412A>G	p.Asn1138Asp	missense_variant	33/182	5	NM_001164507.2	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.3412A>G	p.Asn1138Asp	missense_variant	33/150	5			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

GnomAD3 exomes

AF:

0.00880

AC:

2193

AN:

249156

Hom.:

AF XY:

0.00815

AC XY:

1101

AN XY:

135168

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 SAS exome

AF:

0.00239

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

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0129

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0654

Gnomad4 SAS exome

AF:

0.00213

Gnomad4 FIN exome

AF:

0.00794

Gnomad4 NFE exome

AF:

0.000263

Gnomad4 OTH exome

AF:

0.00543

GnomAD4 genome

AF:

0.00422

AC:

642

AN:

152294

Hom.:

Cov.:

AF XY:

0.00471

AC XY:

351

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.00804

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0687

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.00782

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00348

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

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 24, 2017	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

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

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

MutationTaster

Benign

0.72

N;N;N;N

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

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