rs2296610

Positions:

chr10-20868692-G-T

Variant summary

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

The NM_006393.3(NEBL):c.656C>A(p.Ala219Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00787 in 1,611,660 control chromosomes in the GnomAD database, including 673 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 96 hom., cov: 32)

Exomes 𝑓: 0.0074 ( 577 hom. )

Consequence

NEBL
NM_006393.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 6.86

Variant links:

Genes affected

NEBL (HGNC:16932): (nebulette) This gene encodes a nebulin like protein that is abundantly expressed in cardiac muscle. The encoded protein binds actin and interacts with thin filaments and Z-line associated proteins in striated muscle. This protein may be involved in cardiac myofibril assembly. A shorter isoform of this protein termed LIM nebulette is expressed in non-muscle cells and may function as a component of focal adhesion complexes. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

NEBL links:

NEBL (HGNC:):

NEBL 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=0.0026087463).

BP6

Variant 10-20868692-G-T is Benign according to our data. Variant chr10-20868692-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 45500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20868692-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEBL	NM_006393.3 linkuse as main transcript	c.656C>A	p.Ala219Asp	missense_variant	7/28	ENST00000377122.9	NP_006384.1	O76041-1Q59FZ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000377122.9 linkuse as main transcript	c.656C>A	p.Ala219Asp	missense_variant	7/28	1	NM_006393.3	ENSP00000366326.4		O76041-1

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1916

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0165

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.153

Gnomad SAS

AF:

0.00662

Gnomad FIN

AF:

0.0639

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00147

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.0199

AC:

4988

AN:

251144

Hom.:

279

AF XY:

0.0184

AC XY:

2497

AN XY:

135724

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.0187

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.156

Gnomad SAS exome

AF:

0.00307

Gnomad FIN exome

AF:

0.0522

Gnomad NFE exome

AF:

0.00145

Gnomad OTH exome

AF:

0.0131

GnomAD4 exome

AF:

0.00738

AC:

10775

AN:

1459520

Hom.:

577

Cov.:

AF XY:

0.00719

AC XY:

5219

AN XY:

726252

show subpopulations

Gnomad4 AFR exome

AF:

0.000569

Gnomad4 AMR exome

AF:

0.0190

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.141

Gnomad4 SAS exome

AF:

0.00383

Gnomad4 FIN exome

AF:

0.0511

Gnomad4 NFE exome

AF:

0.000523

Gnomad4 OTH exome

AF:

0.0115

GnomAD4 genome

AF:

0.0126

AC:

1911

AN:

152140

Hom.:

Cov.:

AF XY:

0.0166

AC XY:

1237

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00125

Gnomad4 AMR

AF:

0.0165

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.152

Gnomad4 SAS

AF:

0.00663

Gnomad4 FIN

AF:

0.0639

Gnomad4 NFE

AF:

0.00147

Gnomad4 OTH

AF:

0.00663

Alfa

AF:

0.00561

Hom.:

Bravo

AF:

0.0105

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.0179

AC:

2174

Asia WGS

AF:

0.0640

AC:

220

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2014	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Ala219Asp in Exon 07 of NEBL: This variant is not expected to have clinical si gnificance because it has been identified in 20.7% (17/82) of chromosomes from a population in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs2 296610). -

NEBL-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

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). -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Primary dilated cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 02, 2013

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.6

REVEL

Uncertain

0.45

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.31

MPC

0.13

ClinPred

0.028

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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