NM_006393.3:c.267C>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -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

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

NEBL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 VariationId is 178101.

BS2

High AC in GnomAd4 at 221 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEBL	NM_006393.3 link	c.267C>G	p.Tyr89*	stop_gained	Exon 4 of 28	ENST00000377122.9	NP_006384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000377122.9 link	c.267C>G	p.Tyr89*	stop_gained	Exon 4 of 28	1	NM_006393.3	ENSP00000366326.4

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

GnomAD2 exomes

AF:

0.00126

AC:

315

AN:

249424

AF XY:

0.00130

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 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

African (AFR)

AF:

0.000241

AC:

AN:

33234

American (AMR)

AF:

0.000896

AC:

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39640

South Asian (SAS)

AF:

0.0000822

AC:

AN:

85146

European-Finnish (FIN)

AF:

0.000844

AC:

AN:

53320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00232

AC:

2559

AN:

1102890

Other (OTH)

AF:

0.00127

AC:

AN:

60010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

111

222

332

443

554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00150

AC:

221

AN:

147508

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

106

AN XY:

71854

show subpopulations

African (AFR)

AF:

0.000541

AC:

AN:

38850

American (AMR)

AF:

0.00164

AC:

AN:

14600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5086

South Asian (SAS)

AF:

0.000215

AC:

AN:

4650

European-Finnish (FIN)

AF:

0.000591

AC:

AN:

10144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00246

AC:

166

AN:

67498

Other (OTH)

AF:

0.00148

AC:

AN:

2024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Sep 07, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27662471)

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Uncertain:1Benign:1

Jan 18, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Oct 30, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Distal monosomy 10p

Uncertain:1

Mar 08, 2024

Molecular Genetics Laboratory, Biobizkaia Health Research Institute

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Nov 02, 2015

Blueprint Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEBL-related disorder

Benign:1

Jan 16, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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;C0023976:Long QT syndrome;C0520806:Sudden unexplained death;na:sudden unexplained death in epilepsy

Benign:1

Jun 12, 2018

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

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'.

Hypertrophic cardiomyopathy

Benign:1

Nov 28, 2019

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

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

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;.

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.0

.;.

MetaRNN

Benign

0.0

.;.

MutationAssessor

Benign

0.0

.;.

PhyloP100

1.8

PROVEAN

Benign

0.0

.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.

Sift4G

Pathogenic

0.0

.;.

Vest4

0.77

GERP RS

4.1

Mutation Taster

=137/63

disease causing (fs/PTC)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over