10-20888214-GAAA-GAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_006393.3(NEBL):c.259-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,389,664 control chromosomes in the GnomAD database, including 1,471 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.085 ( 928 hom., cov: 31)

Exomes 𝑓: 0.012 ( 543 hom. )

Consequence

NEBL
NM_006393.3 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.367

Publications

0 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: Benign. The variant received -16 ACMG points.

BP6

Variant 10-20888214-G-GA is Benign according to our data. Variant chr10-20888214-G-GA is described in ClinVar as Benign. ClinVar VariationId is 45495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEBL	NM_006393.3 link	c.259-8dupT		splice_region_variant, intron_variant	Intron 3 of 27	ENST00000377122.9	NP_006384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000377122.9 link	c.259-8_259-7insT		splice_region_variant, intron_variant	Intron 3 of 27	1	NM_006393.3	ENSP00000366326.4

Frequencies

GnomAD3 genomes

AF:

0.0853

AC:

9660

AN:

113292

Hom.:

925

Cov.:

show subpopulations

Gnomad AFR

AF:

0.257

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0352

Gnomad ASJ

AF:

0.0100

Gnomad EAS

AF:

0.0288

Gnomad SAS

AF:

0.00706

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0564

Gnomad NFE

AF:

0.00468

Gnomad OTH

AF:

0.0605

GnomAD2 exomes

AF:

0.0222

AC:

4734

AN:

213600

AF XY:

0.0179

show subpopulations

Gnomad AFR exome

AF:

0.216

Gnomad AMR exome

AF:

0.0182

Gnomad ASJ exome

AF:

0.0106

Gnomad EAS exome

AF:

0.0284

Gnomad FIN exome

AF:

0.0000973

Gnomad NFE exome

AF:

0.00381

Gnomad OTH exome

AF:

0.0173

GnomAD4 exome

AF:

0.0122

AC:

15621

AN:

1276262

Hom.:

543

Cov.:

AF XY:

0.0114

AC XY:

7283

AN XY:

639522

show subpopulations

African (AFR)

AF:

0.211

AC:

6082

AN:

28846

American (AMR)

AF:

0.0181

AC:

736

AN:

40608

Ashkenazi Jewish (ASJ)

AF:

0.0128

AC:

302

AN:

23676

East Asian (EAS)

AF:

0.0309

AC:

1136

AN:

36714

South Asian (SAS)

AF:

0.00689

AC:

533

AN:

77334

European-Finnish (FIN)

AF:

0.000601

AC:

AN:

49912

Middle Eastern (MID)

AF:

0.0255

AC:

133

AN:

5210

European-Non Finnish (NFE)

AF:

0.00571

AC:

5492

AN:

961000

Other (OTH)

AF:

0.0222

AC:

1177

AN:

52962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.427

Heterozygous variant carriers

486

972

1459

1945

2431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

350

700

1050

1400

1750

<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:

0.0854

AC:

9685

AN:

113402

Hom.:

928

Cov.:

AF XY:

0.0847

AC XY:

4628

AN XY:

54608

show subpopulations

African (AFR)

AF:

0.257

AC:

8801

AN:

34206

American (AMR)

AF:

0.0351

AC:

361

AN:

10286

Ashkenazi Jewish (ASJ)

AF:

0.0100

AC:

AN:

2900

East Asian (EAS)

AF:

0.0289

AC:

130

AN:

4502

South Asian (SAS)

AF:

0.00679

AC:

AN:

3386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5638

Middle Eastern (MID)

AF:

0.0520

AC:

AN:

250

European-Non Finnish (NFE)

AF:

0.00468

AC:

234

AN:

50028

Other (OTH)

AF:

0.0606

AC:

AN:

1550

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

364

728

1091

1455

1819

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<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:

0.00775

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 26, 2017

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 14, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.259-8dup in intron 3 of NEBL: This variant is classified as benign because it has been identified in 23% (4831/20832) of African chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs753190853). ACMG/AMP Criteria: BA1. -

Apr 17, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NEBL-related disorder

Benign:1

May 20, 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

Feb 03, 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

PhyloP100

-0.37

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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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