rs71535732

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006393.3(NEBL):c.2182A>G(p.Thr728Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00592 in 1,612,100 control chromosomes in the GnomAD database, including 403 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T728I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0095 ( 47 hom., cov: 33)

Exomes 𝑓: 0.0055 ( 356 hom. )

Consequence

NEBL
NM_006393.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.359

Publications

12 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014253855).

BP6

Variant 10-20815684-T-C is Benign according to our data. Variant chr10-20815684-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0932 is higher than 0.05.

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.2182A>G	p.Thr728Ala	missense	Exon 22 of 28	NP_006384.1	O76041-1
NEBL	NM_001377322.1		c.358-2744A>G		intron	N/A	NP_001364251.1
NEBL	NM_213569.2		c.358-2744A>G		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.2182A>G	p.Thr728Ala	missense	Exon 22 of 28	ENSP00000366326.4	O76041-1
NEBL	ENST00000417816.2	TSL:1	c.358-2744A>G		intron	N/A	ENSP00000393896.2	O76041-2
NEBL	ENST00000493005.5	TSL:1	n.1502A>G		non_coding_transcript_exon	Exon 9 of 12

Frequencies

GnomAD3 genomes

AF:

0.00943

AC:

1436

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0499

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.100

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00956

GnomAD2 exomes

AF:

0.0201

AC:

5041

AN:

250906

AF XY:

0.0168

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.0875

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0985

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000794

Gnomad OTH exome

AF:

0.0114

GnomAD4 exome

AF:

0.00554

AC:

8094

AN:

1459776

Hom.:

356

Cov.:

AF XY:

0.00511

AC XY:

3709

AN XY:

726376

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

33446

American (AMR)

AF:

0.0809

AC:

3619

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.0919

AC:

3644

AN:

39644

South Asian (SAS)

AF:

0.00339

AC:

292

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53262

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000549

AC:

AN:

1110274

Other (OTH)

AF:

0.00729

AC:

440

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

423

847

1270

1694

2117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<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:

0.00952

AC:

1450

AN:

152324

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

834

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00241

AC:

100

AN:

41580

American (AMR)

AF:

0.0507

AC:

776

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.100

AC:

520

AN:

5184

South Asian (SAS)

AF:

0.00352

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68024

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

132

197

263

329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00435

Hom.:

Bravo

AF:

0.0135

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.0164

AC:

1986

Asia WGS

AF:

0.0420

AC:

145

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Cardiovascular phenotype (1)

NEBL-related disorder (1)

not provided (1)

Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.83

CADD

Benign

7.4

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0039

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.0093

LIST_S2

Benign

0.026

MetaRNN

Benign

0.0014

MetaSVM

Benign

-0.89

MutationAssessor

Benign

-1.6

PhyloP100

0.36

PrimateAI

Benign

0.44

PROVEAN

Benign

0.68

REVEL

Benign

0.063

Sift

Benign

0.40

Sift4G

Benign

0.92

Polyphen

0.0

Vest4

0.085

MPC

0.016

ClinPred

0.0019

GERP RS

5.0

Varity_R

0.038

gMVP

0.085

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over