NM_006393.3:c.1269A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_006393.3(NEBL):c.1269A>G(p.Lys423Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000317 in 1,610,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

NEBL
NM_006393.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.20

Publications

1 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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 10-20840808-T-C is Benign according to our data. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20840808-T-C is described in CliVar as Likely_benign. Clinvar id is 164754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.2 with no splicing effect.

BS2

High AC in GnomAdExome4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEBL	NM_006393.3 link	c.1269A>G	p.Lys423Lys	synonymous_variant	Exon 13 of 28	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.1269A>G	p.Lys423Lys	synonymous_variant	Exon 13 of 28	1	NM_006393.3	ENSP00000366326.4		O76041-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249702

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000343

AC:

AN:

1458194

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

725630

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33400

American (AMR)

AF:

0.00

AC:

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39570

South Asian (SAS)

AF:

0.00

AC:

AN:

86140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52892

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

1109480

Other (OTH)

AF:

0.0000166

AC:

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000387

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Nov 27, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Apr 03, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lys423Lys in exon 13 of NEBL: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. -

Primary dilated cardiomyopathy

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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

-0.54

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

1.2

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over