rs41277370

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1132G>C(p.Asp378His) variant causes a missense change. The variant allele was found at a frequency of 0.0731 in 1,588,688 control chromosomes in the GnomAD database, including 4,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D378D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.058 ( 365 hom., cov: 32)

Exomes 𝑓: 0.075 ( 4564 hom. )

Consequence

NEBL
NM_006393.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.21

Publications

14 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

new If you want to explore the variant's impact on the transcript NM_006393.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002236694).

BP6

Variant 10-20845353-C-G is Benign according to our data. Variant chr10-20845353-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.079 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.1132G>C	p.Asp378His	missense	Exon 12 of 28	NP_006384.1	O76041-1
NEBL	NM_001377322.1		c.358-32413G>C		intron	N/A	NP_001364251.1
NEBL	NM_213569.2		c.358-32413G>C		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.1132G>C	p.Asp378His	missense	Exon 12 of 28	ENSP00000366326.4	O76041-1
NEBL	ENST00000417816.2	TSL:1	c.358-32413G>C		intron	N/A	ENSP00000393896.2	O76041-2
NEBL	ENST00000863069.1		c.1132G>C	p.Asp378His	missense	Exon 12 of 28	ENSP00000533128.1

Frequencies

GnomAD3 genomes

AF:

0.0585

AC:

8887

AN:

152030

Hom.:

365

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0189

Gnomad AMI

AF:

0.0484

Gnomad AMR

AF:

0.0539

Gnomad ASJ

AF:

0.185

Gnomad EAS

AF:

0.0225

Gnomad SAS

AF:

0.0660

Gnomad FIN

AF:

0.0432

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0808

Gnomad OTH

AF:

0.0841

GnomAD2 exomes

AF:

0.0664

AC:

16617

AN:

250238

AF XY:

0.0698

show subpopulations

Gnomad AFR exome

AF:

0.0158

Gnomad AMR exome

AF:

0.0426

Gnomad ASJ exome

AF:

0.167

Gnomad EAS exome

AF:

0.0190

Gnomad FIN exome

AF:

0.0462

Gnomad NFE exome

AF:

0.0813

Gnomad OTH exome

AF:

0.0804

GnomAD4 exome

AF:

0.0747

AC:

107242

AN:

1436538

Hom.:

4564

Cov.:

AF XY:

0.0753

AC XY:

53922

AN XY:

716038

show subpopulations

African (AFR)

AF:

0.0190

AC:

626

AN:

32988

American (AMR)

AF:

0.0438

AC:

1952

AN:

44556

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

4342

AN:

25856

East Asian (EAS)

AF:

0.0129

AC:

509

AN:

39470

South Asian (SAS)

AF:

0.0719

AC:

6160

AN:

85682

European-Finnish (FIN)

AF:

0.0473

AC:

2514

AN:

53160

Middle Eastern (MID)

AF:

0.172

AC:

983

AN:

5706

European-Non Finnish (NFE)

AF:

0.0782

AC:

85247

AN:

1089600

Other (OTH)

AF:

0.0825

AC:

4909

AN:

59520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

4316

8631

12947

17262

21578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3078

6156

9234

12312

15390

<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:

0.0584

AC:

8887

AN:

152150

Hom.:

365

Cov.:

AF XY:

0.0569

AC XY:

4230

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0189

AC:

785

AN:

41530

American (AMR)

AF:

0.0538

AC:

821

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.185

AC:

643

AN:

3470

East Asian (EAS)

AF:

0.0228

AC:

118

AN:

5178

South Asian (SAS)

AF:

0.0660

AC:

318

AN:

4818

European-Finnish (FIN)

AF:

0.0432

AC:

458

AN:

10600

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0808

AC:

5489

AN:

67970

Other (OTH)

AF:

0.0833

AC:

176

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

408

816

1224

1632

2040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

208

312

416

520

<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:

0.0723

Hom.:

174

Bravo

AF:

0.0586

Asia WGS

AF:

0.0470

AC:

164

AN:

3476

EpiCase

AF:

0.0894

EpiControl

AF:

0.0950

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

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

Uncertain

0.37

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.045

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0022

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.9

PhyloP100

4.2

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-5.7

REVEL

Benign

0.22

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0010

Varity_R

0.51

gMVP

0.41

Mutation Taster

=91/9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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