10-20823208-A-T

Position:

chr10-20823208-A-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.1962T>A(p.Asn654Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0383 in 1,596,352 control chromosomes in the GnomAD database, including 3,014 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.079 ( 901 hom., cov: 32)

Exomes 𝑓: 0.034 ( 2113 hom. )

Consequence

NEBL
NM_006393.3 missense, splice_region

Scores

Splicing: ADA: 0.6236

Clinical Significance

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

Conservation

PhyloP100: 0.915

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=0.0017476678).

BP6

Variant 10-20823208-A-T is Benign according to our data. Variant chr10-20823208-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 45488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEBL	NM_006393.3 link	c.1962T>A	p.Asn654Lys	missense_variant, splice_region_variant	19/28	ENST00000377122.9	NP_006384.1	O76041-1Q59FZ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000377122.9 link	c.1962T>A	p.Asn654Lys	missense_variant, splice_region_variant	19/28	1	NM_006393.3	ENSP00000366326.4		O76041-1

Frequencies

GnomAD3 genomes

AF:

0.0787

AC:

11969

AN:

152112

Hom.:

889

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0671

Gnomad ASJ

AF:

0.0132

Gnomad EAS

AF:

0.117

Gnomad SAS

AF:

0.0942

Gnomad FIN

AF:

0.0266

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0211

Gnomad OTH

AF:

0.0751

GnomAD3 exomes

AF:

0.0565

AC:

14044

AN:

248674

Hom.:

769

AF XY:

0.0543

AC XY:

7310

AN XY:

134536

show subpopulations

Gnomad AFR exome

AF:

0.200

Gnomad AMR exome

AF:

0.0720

Gnomad ASJ exome

AF:

0.0172

Gnomad EAS exome

AF:

0.114

Gnomad SAS exome

AF:

0.0903

Gnomad FIN exome

AF:

0.0281

Gnomad NFE exome

AF:

0.0220

Gnomad OTH exome

AF:

0.0414

GnomAD4 exome

AF:

0.0340

AC:

49110

AN:

1444122

Hom.:

2113

Cov.:

AF XY:

0.0351

AC XY:

25265

AN XY:

719334

show subpopulations

Gnomad4 AFR exome

AF:

0.204

Gnomad4 AMR exome

AF:

0.0728

Gnomad4 ASJ exome

AF:

0.0174

Gnomad4 EAS exome

AF:

0.137

Gnomad4 SAS exome

AF:

0.0893

Gnomad4 FIN exome

AF:

0.0262

Gnomad4 NFE exome

AF:

0.0194

Gnomad4 OTH exome

AF:

0.0459

GnomAD4 genome

AF:

0.0790

AC:

12021

AN:

152230

Hom.:

901

Cov.:

AF XY:

0.0789

AC XY:

5875

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.192

Gnomad4 AMR

AF:

0.0669

Gnomad4 ASJ

AF:

0.0132

Gnomad4 EAS

AF:

0.118

Gnomad4 SAS

AF:

0.0945

Gnomad4 FIN

AF:

0.0266

Gnomad4 NFE

AF:

0.0211

Gnomad4 OTH

AF:

0.0814

Alfa

AF:

0.0308

Hom.:

250

Bravo

AF:

0.0887

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0197

AC:

ESP6500AA

AF:

0.192

AC:

848

ESP6500EA

AF:

0.0224

AC:

193

ExAC

AF:

0.0593

AC:

7204

Asia WGS

AF:

0.160

AC:

560

AN:

3478

EpiCase

AF:

0.0246

EpiControl

AF:

0.0242

ClinVar

Significance: Benign/Likely 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	GeneDx	Dec 19, 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. -
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	Ambry Genetics	Feb 07, 2019	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Asn654Lys in Exon 19 of NEBL: This variant is not expected to have clinical si gnificance because it has been identified in 19.0% (709/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs4748728). -

NEBL-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0062

Eigen

Benign

0.0089

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.9

REVEL

Benign

0.082

Sift

Benign

0.057

Sift4G

Benign

0.20

Polyphen

0.032

Vest4

0.061

MutPred

0.24

Loss of ubiquitination at K650 (P = 0.0162);

MPC

0.017

ClinPred

0.022

GERP RS

4.8

Varity_R

0.14

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.62

SpliceAI score (max)

0.060

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