10-20828531-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_006393.3(NEBL):c.1775C>A(p.Ala592Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 1,561,152 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A592V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00096 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

NEBL
NM_006393.3 missense, splice_region

Scores

Splicing: ADA: 0.00004499

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 0.495

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.051025182).

BP6

Variant 10-20828531-G-T is Benign according to our data. Variant chr10-20828531-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45485.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr10-20828531-G-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEBL	NM_006393.3 linkuse as main transcript	c.1775C>A	p.Ala592Glu	missense_variant, splice_region_variant	17/28	ENST00000377122.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEBL	ENST00000377122.9 linkuse as main transcript	c.1775C>A	p.Ala592Glu	missense_variant, splice_region_variant	17/28	1	NM_006393.3		O76041-1

Frequencies

GnomAD3 genomes

AF:

0.000953

AC:

145

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

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:

0.0000147

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000268

AC:

AN:

249848

Hom.:

AF XY:

0.000252

AC XY:

AN XY:

135080

show subpopulations

Gnomad AFR exome

AF:

0.00315

Gnomad AMR exome

AF:

0.000262

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000122

AC:

172

AN:

1408926

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

703974

show subpopulations

Gnomad4 AFR exome

AF:

0.00348

Gnomad4 AMR exome

AF:

0.000427

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000272

Gnomad4 OTH exome

AF:

0.000188

GnomAD4 genome

AF:

0.000959

AC:

146

AN:

152226

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00325

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.0000931

Hom.:

Bravo

AF:

0.00112

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2022	Originally reported in a female patient with neonatal DCM who also harbored a missense variant in the ACTN2 gene (Purevjav et al., 2010); Subsequently reported in a 23-year-old female with possible arrhythmogenic right ventricular cardiomyopathy (ARVC) (Medeiros-Domingo et al., 2016); Mouse models harboring the p.(A592E) variant exhibited DCM and impaired cardiac function (Purevjav et al., 2010; Maiellaro-Rafferty et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 23299917, 23632046, 25525159, 27186169, 27896284, 27194543, 25987543, 27733623, 21430528, 33861145, 20951326, 26582918, 26321576) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2013

The p.A592E variant (also known as c.1775C>A) is located in coding exon 17 of the NEBL gene. This alteration results from a C to A substitution at nucleotide position 1775, which is the second to last nucleotide position in exon 17. The alanine at codon 592 is replaced by glutamate, an amino acid with dissimilar properties. In one study, the p.A592E variant was detected in conjunction with a digenic mutation in ACTN2 in a patient diagnosed in the newborn period with dilated cardiomyopathy (DCM). The authors describe p.A592E transgenic mice (A592E-Tg), which displayed signs of DCM. By 6 months of age, the A592E-Tg mice displayed significantly decreased running distances compared to transgenic-wild type (WT-Tg) and non-transgenic mice (non-Tg) (p < 0.01). Significant fractional shortening was observed in A592E-Tg mice compared to non-TG and WT-Tg mice (p < 0.05). Significant dilatation of the left ventricle was also observed in A592E-Tg mice. In addition, Z-disk-associated proteins appeared to be downregulated and more disrupted in A592E-Tg hearts upon protein expression assays (Purevjav et al. 2010 JACC 56(18):1493-502).This variant was previously reported in the SNPDatabase as rs146275785. Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.13% (17/13004), having been observed in 0.36% (13/4406) of African American alleles, and in 0.01% (1/8598) of European American alleles studied. Based on data from the 1000 Genomes Project, the A-allele has an overall frequency of approximately 0.05% (1/2184). The highest observed frequency was 0.57% (1/176) of Yoruban West African chromosomes studied.Based on nucleotide alignment in available species, this nucleotide position is poorly conserved. Based on protein sequence alignment in available, this amino acid position is poorly conserved. Using the BDGP and ESEfinder splice site prediction tools, this alteration does not have any significant effect on the native acceptor splice site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is unlikely to be pathogenic. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence for this variant is conflicting at this time, the clinical significance remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 17, 2016

p.Ala592Glu in exon 17 of NEBL: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (28/10104) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs146275785). -

NEBL-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 16, 2023

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

Invitae

Dec 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

Cadd

Benign

6.8

Dann

Benign

0.44

DEOGEN2

Benign

0.0050

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.060

M_CAP

Benign

0.0046

MetaRNN

Benign

0.051

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.3

REVEL

Benign

0.27

Sift

Benign

0.076

Sift4G

Benign

0.069

Polyphen

0.013

Vest4

0.75

MVP

0.10

MPC

0.017

ClinPred

0.0016

GERP RS

-2.5

Varity_R

0.12

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000045

dbscSNV1_RF

Benign

0.17

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