rs114875104

Positions:

chr10-20817668-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006393.3(NEBL):c.2080C>T(p.Arg694Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,613,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

NEBL
NM_006393.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 0.228

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.017885596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEBL	NM_006393.3 linkuse as main transcript	c.2080C>T	p.Arg694Trp	missense_variant	21/28	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.2080C>T	p.Arg694Trp	missense_variant	21/28	1	NM_006393.3	ENSP00000366326.4		O76041-1

Frequencies

GnomAD3 genomes

AF:

0.000559

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00184

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251062

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000142

AC:

207

AN:

1461216

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

726984

show subpopulations

Gnomad4 AFR exome

AF:

0.00170

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000105

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000558

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00183

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000311

Hom.:

Bravo

AF:

0.000650

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 23, 2013	Variant classified as Uncertain Significance - Favor Benign. The Arg694Trp varia nt in NEBL has not been reported in the literature nor previously identified by our laboratory. This variant has been identified in 0.16% (7/4406) of African Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs114875104). This frequency is too l ow to rule out a role in disease. Arginine (Arg) at position 694 is not conserve d in evolution, suggesting that a change to this position may be tolerated. This variant is less likely disease causing but additional studies are needed to ful ly assess its clinical significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 01, 2021	The c.2080C>T (p.R694W) alteration is located in exon 21 (coding exon 21) of the NEBL gene. This alteration results from a C to T substitution at nucleotide position 2080, causing the arginine (R) at amino acid position 694 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2017	A variant of uncertain significance has been identified in the NEBL gene. The R694W variant has not been published as a pathogenic variant or reported as a benign variant, to our knowledge. The NHLBI Exome Sequencing Project, Exome Aggregation Consortium (ExAC) and the 1000 Genomes Project reports R694W was observed in 0.1-0.2% of individuals of African background, indicating it may be a rare (benign) variant in this population. This substitution occurs at a position that is not conserved across species. Nevertheless, the R694W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, in silico analysis predicts this variant is probably damaging to the protein structure/function. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	NEBL NM_006393.2 exon 25 p.Arg694Trp (c.2080C>T): This variant has not been reported in the literature and is present in 0.1% (38/24960) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/10-21106597-G-A). This variant is present in ClinVar (Variation ID:45491). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

NEBL-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 24, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Primary dilated cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.097

Eigen

Benign

0.036

Eigen_PC

Benign

-0.0089

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.32

M_CAP

Benign

0.015

MetaRNN

Benign

0.018

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.067

Sift

Uncertain

0.023

Sift4G

Uncertain

0.0070

Polyphen

0.94

Vest4

0.28

MVP

0.45

MPC

0.055

ClinPred

0.055

GERP RS

4.1

Varity_R

0.14

gMVP

0.17

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