Genetic Variant NM_006393.3:c.1450-9T>G (chr10-20831592-A-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_006393.3(NEBL):c.1450-9T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000981 in 1,550,754 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 4 hom., cov: 31)

Exomes 𝑓: 0.00079 ( 2 hom. )

Consequence

NEBL
NM_006393.3 intron

Scores

Splicing: ADA: 0.7220

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.365

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.23).

BP6

Variant 10-20831592-A-C is Benign according to our data. Variant chr10-20831592-A-C is described in ClinVar as [Benign]. Clinvar id is 164752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20831592-A-C is described in Lovd as [Benign]. Variant chr10-20831592-A-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEBL	NM_006393.3 link	c.1450-9T>G		intron_variant	Intron 14 of 27	ENST00000377122.9	NP_006384.1	O76041-1Q59FZ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000377122.9 link	c.1450-9T>G		intron_variant	Intron 14 of 27	1	NM_006393.3	ENSP00000366326.4		O76041-1

Frequencies

GnomAD3 genomes

AF:

0.00269

AC:

409

AN:

151866

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00719

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00296

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00384

GnomAD3 exomes

AF:

0.00139

AC:

347

AN:

249808

Hom.:

AF XY:

0.00117

AC XY:

158

AN XY:

135022

show subpopulations

Gnomad AFR exome

AF:

0.00868

Gnomad AMR exome

AF:

0.00230

Gnomad ASJ exome

AF:

0.00498

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000584

Gnomad OTH exome

AF:

0.00181

GnomAD4 exome

AF:

0.000794

AC:

1111

AN:

1398770

Hom.:

Cov.:

AF XY:

0.000799

AC XY:

559

AN XY:

699632

show subpopulations

Gnomad4 AFR exome

AF:

0.00876

Gnomad4 AMR exome

AF:

0.00263

Gnomad4 ASJ exome

AF:

0.00454

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.000425

Gnomad4 OTH exome

AF:

0.00214

GnomAD4 genome

AF:

0.00270

AC:

411

AN:

151984

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

186

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.00724

Gnomad4 AMR

AF:

0.00289

Gnomad4 ASJ

AF:

0.00663

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.00380

Alfa

AF:

0.00171

Hom.:

Bravo

AF:

0.00317

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Aug 28, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.1450-9T>G in Intron 14 of NEBL: This variant is not expected to have clinical significance because it has been identified in 17.5% (7/40) of chromosomes from a population in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs 45628140). -

Mar 03, 2024

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

NEBL-related disorder

Benign:1

Feb 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.72

dbscSNV1_RF

Benign

0.50

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