NM_006393.3:c.604G>A

Variant names:

Variant summary

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

The NM_006393.3(NEBL):c.604G>A(p.Gly202Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,607,228 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 4 hom. )

Consequence

NEBL
NM_006393.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 1.59

Publications

20 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=0.030071944).

BP6

Variant 10-20868744-C-T is Benign according to our data. Variant chr10-20868744-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45499.

BS2

High AC in GnomAd4 at 312 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.604G>A	p.Gly202Arg	missense	Exon 7 of 28	NP_006384.1	O76041-1
NEBL	NM_001377322.1		c.358-55804G>A		intron	N/A	NP_001364251.1
NEBL	NM_213569.2		c.358-55804G>A		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.604G>A	p.Gly202Arg	missense	Exon 7 of 28	ENSP00000366326.4	O76041-1
NEBL	ENST00000417816.2	TSL:1	c.358-55804G>A		intron	N/A	ENSP00000393896.2	O76041-2
NEBL	ENST00000863069.1		c.604G>A	p.Gly202Arg	missense	Exon 7 of 28	ENSP00000533128.1

Frequencies

GnomAD3 genomes

AF:

0.00206

AC:

313

AN:

151822

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000677

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00342

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00105

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00293

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00208

AC:

521

AN:

251076

AF XY:

0.00187

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00272

Gnomad ASJ exome

AF:

0.00318

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00166

Gnomad NFE exome

AF:

0.00288

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00231

AC:

3362

AN:

1455290

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

1636

AN XY:

724492

show subpopulations

African (AFR)

AF:

0.000631

AC:

AN:

33266

American (AMR)

AF:

0.00277

AC:

124

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00295

AC:

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39584

South Asian (SAS)

AF:

0.000186

AC:

AN:

86116

European-Finnish (FIN)

AF:

0.00176

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00331

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00258

AC:

2857

AN:

1106240

Other (OTH)

AF:

0.00256

AC:

154

AN:

60172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

154

309

463

618

772

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

200

300

400

500

<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:

0.00205

AC:

312

AN:

151938

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.000675

AC:

AN:

41456

American (AMR)

AF:

0.00341

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00105

AC:

AN:

10524

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00293

AC:

199

AN:

67954

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.00232

Hom.:

Bravo

AF:

0.00212

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00213

AC:

258

Asia WGS

AF:

0.000578

AC:

AN:

3474

EpiCase

AF:

0.00365

EpiControl

AF:

0.00308

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (3)

NEBL-related disorder (1)

Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.012

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.084

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.84

M_CAP

Benign

0.0087

MetaRNN

Benign

0.030

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

1.6

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.48

REVEL

Benign

0.19

Sift

Benign

0.46

Sift4G

Benign

0.21

Polyphen

0.0010

Vest4

0.72

MutPred

0.36

Gain of MoRF binding (P = 0.0038)

MVP

0.31

MPC

0.017

ClinPred

0.0062

GERP RS

4.2

Varity_R

0.086

gMVP

0.32

Mutation Taster

=86/14

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

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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