10-20845353-C-G

Position:

chr10-20845353-C-G

Variant summary

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

The ENST00000377122.9(NEBL):c.1132G>C(p.Asp378His) variant causes a missense change. The variant allele was found at a frequency of 0.0731 in 1,588,688 control chromosomes in the GnomAD database, including 4,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.058 ( 365 hom., cov: 32)

Exomes 𝑓: 0.075 ( 4564 hom. )

Consequence

NEBL
ENST00000377122.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.21

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:

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=0.002236694).

BP6

Variant 10-20845353-C-G is Benign according to our data. Variant chr10-20845353-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 45475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.079 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.1132G>C	p.Asp378His	missense_variant	12/28	ENST00000377122.9	NP_006384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000377122.9 linkuse as main transcript	c.1132G>C	p.Asp378His	missense_variant	12/28	1	NM_006393.3	ENSP00000366326		O76041-1

Frequencies

GnomAD3 genomes

AF:

0.0585

AC:

8887

AN:

152030

Hom.:

365

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0189

Gnomad AMI

AF:

0.0484

Gnomad AMR

AF:

0.0539

Gnomad ASJ

AF:

0.185

Gnomad EAS

AF:

0.0225

Gnomad SAS

AF:

0.0660

Gnomad FIN

AF:

0.0432

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0808

Gnomad OTH

AF:

0.0841

GnomAD3 exomes

AF:

0.0664

AC:

16617

AN:

250238

Hom.:

684

AF XY:

0.0698

AC XY:

9448

AN XY:

135282

show subpopulations

Gnomad AFR exome

AF:

0.0158

Gnomad AMR exome

AF:

0.0426

Gnomad ASJ exome

AF:

0.167

Gnomad EAS exome

AF:

0.0190

Gnomad SAS exome

AF:

0.0719

Gnomad FIN exome

AF:

0.0462

Gnomad NFE exome

AF:

0.0813

Gnomad OTH exome

AF:

0.0804

GnomAD4 exome

AF:

0.0747

AC:

107242

AN:

1436538

Hom.:

4564

Cov.:

AF XY:

0.0753

AC XY:

53922

AN XY:

716038

show subpopulations

Gnomad4 AFR exome

AF:

0.0190

Gnomad4 AMR exome

AF:

0.0438

Gnomad4 ASJ exome

AF:

0.168

Gnomad4 EAS exome

AF:

0.0129

Gnomad4 SAS exome

AF:

0.0719

Gnomad4 FIN exome

AF:

0.0473

Gnomad4 NFE exome

AF:

0.0782

Gnomad4 OTH exome

AF:

0.0825

GnomAD4 genome

AF:

0.0584

AC:

8887

AN:

152150

Hom.:

365

Cov.:

AF XY:

0.0569

AC XY:

4230

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0189

Gnomad4 AMR

AF:

0.0538

Gnomad4 ASJ

AF:

0.185

Gnomad4 EAS

AF:

0.0228

Gnomad4 SAS

AF:

0.0660

Gnomad4 FIN

AF:

0.0432

Gnomad4 NFE

AF:

0.0808

Gnomad4 OTH

AF:

0.0833

Alfa

AF:

0.0723

Hom.:

174

Bravo

AF:

0.0586

TwinsUK

AF:

0.0717

AC:

266

ALSPAC

AF:

0.0825

AC:

318

ESP6500AA

AF:

0.0184

AC:

ESP6500EA

AF:

0.0828

AC:

712

ExAC

AF:

0.0648

AC:

7866

Asia WGS

AF:

0.0470

AC:

164

AN:

3476

EpiCase

AF:

0.0894

EpiControl

AF:

0.0950

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Asp378His in Exon 12 of NEBL: This variant is not expected to have clinical si gnificance because it has been identified in 8.2% (578/7018) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs41277370). -
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 04, 2023	- -

NEBL-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 26, 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

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2012

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

Uncertain

0.37

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.045

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0022

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.9

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-5.7

REVEL

Benign

0.22

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0010

Polyphen

0.91

Vest4

0.21

MPC

0.10

ClinPred

0.027

GERP RS

4.2

Varity_R

0.51

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