rs2288200

Positions:

chr2-151547704-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001164508.2(NEB):c.20192A>T(p.Asp6731Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,613,510 control chromosomes in the GnomAD database, including 1,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 404 hom., cov: 31)

Exomes 𝑓: 0.014 ( 1033 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.67

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=0.0018514097).

BP6

Variant 2-151547704-T-A is Benign according to our data. Variant chr2-151547704-T-A is described in ClinVar as [Benign]. Clinvar id is 129721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151547704-T-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.20192A>T	p.Asp6731Val	missense_variant	132/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.20192A>T	p.Asp6731Val	missense_variant	132/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 link	c.20192A>T	p.Asp6731Val	missense_variant	132/182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 link	c.20192A>T	p.Asp6731Val	missense_variant	132/182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.0444

AC:

6751

AN:

152096

Hom.:

392

Cov.:

show subpopulations

Gnomad AFR

AF:

0.120

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0195

Gnomad ASJ

AF:

0.0320

Gnomad EAS

AF:

0.145

Gnomad SAS

AF:

0.0774

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00223

Gnomad OTH

AF:

0.0444

GnomAD3 exomes

AF:

0.0305

AC:

7567

AN:

247902

Hom.:

406

AF XY:

0.0309

AC XY:

4149

AN XY:

134480

show subpopulations

Gnomad AFR exome

AF:

0.122

Gnomad AMR exome

AF:

0.00865

Gnomad ASJ exome

AF:

0.0324

Gnomad EAS exome

AF:

0.147

Gnomad SAS exome

AF:

0.0678

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00219

Gnomad OTH exome

AF:

0.0190

GnomAD4 exome

AF:

0.0140

AC:

20443

AN:

1461296

Hom.:

1033

Cov.:

AF XY:

0.0154

AC XY:

11176

AN XY:

726914

show subpopulations

Gnomad4 AFR exome

AF:

0.127

Gnomad4 AMR exome

AF:

0.00906

Gnomad4 ASJ exome

AF:

0.0324

Gnomad4 EAS exome

AF:

0.138

Gnomad4 SAS exome

AF:

0.0688

Gnomad4 FIN exome

AF:

0.000356

Gnomad4 NFE exome

AF:

0.00162

Gnomad4 OTH exome

AF:

0.0269

GnomAD4 genome

AF:

0.0446

AC:

6786

AN:

152214

Hom.:

404

Cov.:

AF XY:

0.0450

AC XY:

3352

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.120

Gnomad4 AMR

AF:

0.0194

Gnomad4 ASJ

AF:

0.0320

Gnomad4 EAS

AF:

0.146

Gnomad4 SAS

AF:

0.0780

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00223

Gnomad4 OTH

AF:

0.0539

Alfa

AF:

0.0158

Hom.:

Bravo

AF:

0.0486

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.118

AC:

446

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.0333

AC:

4018

Asia WGS

AF:

0.137

AC:

474

AN:

3478

EpiCase

AF:

0.00382

EpiControl

AF:

0.00314

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.Asp6731Val in exon 132 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 11.8% (446/3794) of African Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs2288200). -
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	PreventionGenetics, part of Exact Sciences	Mar 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 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. -

Nemaline myopathy 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

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

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

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

MetaRNN

Benign

0.0019

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

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

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-4.2

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

REVEL

Uncertain

0.47

Sift

Benign

0.063

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.84

MPC

0.40

ClinPred

0.016

GERP RS

5.9

Varity_R

0.53

gMVP

0.43

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