10-20852540-T-C

Position:

chr10-20852540-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006393.3(NEBL):c.1008+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.989 in 1,608,006 control chromosomes in the GnomAD database, including 788,165 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.98 ( 73304 hom., cov: 31)

Exomes 𝑓: 0.99 ( 714861 hom. )

Consequence

NEBL
NM_006393.3 splice_region, intron

Scores

Splicing: ADA: 0.0007574

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.412

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 10-20852540-T-C is Benign according to our data. Variant chr10-20852540-T-C is described in ClinVar as [Benign]. Clinvar id is 45471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEBL	NM_006393.3 linkuse as main transcript	c.1008+5A>G		splice_region_variant, intron_variant		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.1008+5A>G		splice_region_variant, intron_variant		1	NM_006393.3	ENSP00000366326.4		O76041-1

Frequencies

GnomAD3 genomes

AF:

0.981

AC:

149204

AN:

152158

Hom.:

73261

Cov.:

show subpopulations

Gnomad AFR

AF:

0.980

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.903

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

0.902

Gnomad SAS

AF:

0.988

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

0.999

Gnomad OTH

AF:

0.973

GnomAD3 exomes

AF:

0.964

AC:

241060

AN:

250054

Hom.:

116817

AF XY:

0.971

AC XY:

131407

AN XY:

135282

show subpopulations

Gnomad AFR exome

AF:

0.980

Gnomad AMR exome

AF:

0.813

Gnomad ASJ exome

AF:

0.999

Gnomad EAS exome

AF:

0.909

Gnomad SAS exome

AF:

0.990

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.999

Gnomad OTH exome

AF:

0.976

GnomAD4 exome

AF:

0.990

AC:

1441662

AN:

1455730

Hom.:

714861

Cov.:

AF XY:

0.991

AC XY:

718287

AN XY:

724684

show subpopulations

Gnomad4 AFR exome

AF:

0.982

Gnomad4 AMR exome

AF:

0.822

Gnomad4 ASJ exome

AF:

0.999

Gnomad4 EAS exome

AF:

0.914

Gnomad4 SAS exome

AF:

0.991

Gnomad4 FIN exome

AF:

1.00

Gnomad4 NFE exome

AF:

1.00

Gnomad4 OTH exome

AF:

0.986

GnomAD4 genome

AF:

0.980

AC:

149303

AN:

152276

Hom.:

73304

Cov.:

AF XY:

0.979

AC XY:

72915

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.980

Gnomad4 AMR

AF:

0.903

Gnomad4 ASJ

AF:

1.00

Gnomad4 EAS

AF:

0.902

Gnomad4 SAS

AF:

0.988

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

0.999

Gnomad4 OTH

AF:

0.973

Alfa

AF:

0.992

Hom.:

132902

Bravo

AF:

0.971

Asia WGS

AF:

0.952

AC:

3312

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 07, 2019	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	c.1008+5A>G in Intron 10 of NEBL: This variant is not expected to have clinical significance because it has been identified in 2.0% (75/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs703089). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2013	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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Primary dilated cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

DANN

Benign

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00076

dbscSNV1_RF

Benign

0.036

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.26

Position offset: 5

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