rs146218038

Positions:

chr10-20819425-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_006393.3(NEBL):c.2054C>T(p.Ala685Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

NEBL
NM_006393.3 missense, splice_region

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.483

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 -10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.005041331).

BP6

Variant 10-20819425-G-A is Benign according to our data. Variant chr10-20819425-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEBL	NM_006393.3 link	c.2054C>T	p.Ala685Val	missense_variant, splice_region_variant	20/28	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.2054C>T	p.Ala685Val	missense_variant, splice_region_variant	20/28	1	NM_006393.3	ENSP00000366326.4		O76041-1

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000298

AC:

AN:

251260

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00222

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000129

AC:

189

AN:

1461748

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.000837

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00195

Gnomad4 NFE exome

AF:

0.0000360

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000493

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00116

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00189

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000882

Hom.:

Bravo

AF:

0.000453

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000305

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 22, 2017

p.Ala685Val in exon 20 of NEBL: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of note, orangutan, Chinese tree shrew, naked mole rat and rabbit have a valine (Va l) at this position despite high nearby amino acid conservation. In addition, co mputational prediction tools do not suggest a high likelihood of impact to the p rotein. In addition, this variant has been identified in 0.2% (55/25788) of Eur opean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broa dinstitute.org; dbSNP rs146218038). BA1, BP4 -

NEBL-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2024

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). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2019

- -

Primary dilated cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.0081

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.16

M_CAP

Benign

0.0090

MetaRNN

Benign

0.0050

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.83

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.9

REVEL

Benign

0.066

Sift

Benign

0.063

Sift4G

Benign

0.43

Polyphen

0.0

Vest4

0.11

MVP

0.30

MPC

0.016

ClinPred

0.0053

GERP RS

-6.6

Varity_R

0.050

gMVP

0.088

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