10-20888199-G-C

Position:

chr10-20888199-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_006393.3(NEBL):c.267C>G(p.Tyr89*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,598,200 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0015 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 8 hom. )

Consequence

NEBL
NM_006393.3 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:10

Conservation

PhyloP100: 1.78

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 -5 ACMG points.

BP6

Variant 10-20888199-G-C is Benign according to our data. Variant chr10-20888199-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178101.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=2}. Variant chr10-20888199-G-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEBL	NM_006393.3 linkuse as main transcript	c.267C>G	p.Tyr89*	stop_gained	4/28	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.267C>G	p.Tyr89*	stop_gained	4/28	1	NM_006393.3	ENSP00000366326.4		O76041-1

Frequencies

GnomAD3 genomes

AF:

0.00150

AC:

221

AN:

147394

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000542

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00165

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000215

Gnomad FIN

AF:

0.000591

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00246

Gnomad OTH

AF:

0.00150

GnomAD3 exomes

AF:

0.00126

AC:

315

AN:

249424

Hom.:

AF XY:

0.00130

AC XY:

175

AN XY:

134632

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.000583

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000694

Gnomad NFE exome

AF:

0.00234

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00189

AC:

2735

AN:

1450692

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

1326

AN XY:

722194

show subpopulations

Gnomad4 AFR exome

AF:

0.000241

Gnomad4 AMR exome

AF:

0.000896

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000822

Gnomad4 FIN exome

AF:

0.000844

Gnomad4 NFE exome

AF:

0.00232

Gnomad4 OTH exome

AF:

0.00127

GnomAD4 genome

AF:

0.00150

AC:

221

AN:

147508

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

106

AN XY:

71854

show subpopulations

Gnomad4 AFR

AF:

0.000541

Gnomad4 AMR

AF:

0.00164

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000215

Gnomad4 FIN

AF:

0.000591

Gnomad4 NFE

AF:

0.00246

Gnomad4 OTH

AF:

0.00148

Alfa

AF:

0.00148

Hom.:

Bravo

AF:

0.00157

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00129

AC:

157

EpiCase

AF:

0.00236

EpiControl

AF:

0.00267

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2021	This variant is associated with the following publications: (PMID: 27662471) -
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	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 18, 2019	Variant classified as Uncertain Significance - Favor Benign. The p.Tyr89X varian t in NEBL has been identified in 2 individuals with HCM and 1 individual with LV H (LMM data). It has also been identified in 0.24% (305/128294) of European chro mosomes by by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant l eads to a premature termination codon at position 89, which is predicted to lead to a truncated or absent protein; however, this variant does not occur in all t ranscripts of the gene. In addition, the association of variants in NEBL with ca rdiomyopathy has not been clearly established. In summary, while the clinical si gnificance of the p.Tyr89X variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 30, 2023	Variant summary: NEBL c.267C>G (p.Tyr89X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss-of-function variants in NEBL as causative of disease. The variant allele was found at a frequency of 0.0013 in 249424 control chromosomes (gnomAD). The observed variant frequency is approximately 162-fold of the estimated maximal expected allele frequency for a pathogenic variant in NEBL causing Dilated Cardiomyopathy phenotype (7.8e-06), strongly suggesting that the variant is benign. c.267C>G has been reported in the literature in an individual affected with Dilated Cardiomyopathy and an individual with Restrictive Cardiomyopathy, both of whom had variants considered to be likely pathogenic/pathogenic reported in other cardiac-related genes, providing supporting evidence for a benign role (e.g. Kostareva_2016, Forleo_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28750076, 27662471, 33762593). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Four submitters classified the variant as benign/likely benign and two classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Primary dilated cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely benign. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, loss of function is an unlikely mechanism of disease, as null mouse models have normal cardiac function (PMID: 25987543). (I) 0107 - This gene is associated with autosomal dominant disease (PMID: 27186169). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0219 - This variant is non-coding in an alternative transcript, which is the longest (NCBI, UCSC). (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of dilated cardiomyopathy (gnomAD v3; 202 heterozygotes, 5 homozygotes). (SB) 0710 - Other NMD-predicted variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. These variants have been reported mostly as VUS (ClinVar). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been observed in several patients within cardiac disease cohorts, but has been classified as likely benign, benign and as a VUS (ClinVar, PMID: 27662471, PMID: 28750076). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Distal monosomy 10p

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, Biobizkaia Health Research Institute

Mar 08, 2024

- -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 02, 2015

- -

Hypertrophic cardiomyopathy;C0023976:Long QT syndrome;C0520806:Sudden unexplained death

Benign:1

Benign, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Jun 12, 2018

This variant has been identified in 4 probands with different clinical presentations (Long QT syndrome, hypertrophic cardiomyopathy, sudden unexplained death in epilepsy and sudden unxeplained death in a young person) which suggests that this variant is an incidental finding. Furthermore the variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.00128, which is much higher then the frequency of any inherited cardiac condition, therefore we classify NEBL p.Tyr89Ter as 'benign'. -

NEBL-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 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). -

Hypertrophic cardiomyopathy

Benign:1

Benign, no assertion criteria provided

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Nov 28, 2019

The NEBL Tyr89Ter variant if found at a high allele frequency in the the Genome Aggregation Database (MAF=0.0013; http://gnomad.broadinstitute.org/). We identified this variant in a female HCM patient, however the variant did not segregate to another affected family member. Based on high allele frequencies in the general population and our familial data, we classify NEBL Tyr89Ter as "benign". -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.79

Vest4

0.77

GERP RS

4.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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