rs139809958

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006393.3(NEBL):c.383A>T(p.Gln128Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00007 in 1,614,058 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q128R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 1 hom. )

Consequence

NEBL
NM_006393.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 5.83

Publications

8 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:

LOC102725112 (HGNC:):

LOC102725112 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0270859).

BP6

Variant 10-20880891-T-A is Benign according to our data. Variant chr10-20880891-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 229049.

BS2

High AC in GnomAd4 at 71 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006393.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEBL	NM_006393.3	MANE Select	c.383A>T	p.Gln128Leu	missense	Exon 5 of 28	NP_006384.1	O76041-1
NEBL	NM_001377322.1		c.358-67951A>T		intron	N/A	NP_001364251.1
NEBL	NM_213569.2		c.358-67951A>T		intron	N/A	NP_998734.1	Q59FZ8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEBL	ENST00000377122.9	TSL:1 MANE Select	c.383A>T	p.Gln128Leu	missense	Exon 5 of 28	ENSP00000366326.4	O76041-1
NEBL	ENST00000417816.2	TSL:1	c.358-67951A>T		intron	N/A	ENSP00000393896.2	O76041-2
NEBL	ENST00000863069.1		c.383A>T	p.Gln128Leu	missense	Exon 5 of 28	ENSP00000533128.1

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000115

AC:

AN:

251328

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.000896

AC:

AN:

33478

American (AMR)

AF:

0.000179

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111918

Other (OTH)

AF:

0.0000331

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000466

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

41580

American (AMR)

AF:

0.000392

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000506

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000173

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

not provided (1)

Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.088

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.77

M_CAP

Benign

0.030

MetaRNN

Benign

0.027

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.6

PhyloP100

5.8

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-4.3

REVEL

Benign

0.19

Sift

Benign

0.16

Sift4G

Uncertain

0.016

Polyphen

0.12

Vest4

0.57

MVP

0.59

MPC

0.098

ClinPred

0.12

GERP RS

5.8

Varity_R

0.41

gMVP

0.58

Mutation Taster

=69/31

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over