10-20889923-C-G

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.180G>C(p.Lys60Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00549 in 1,607,010 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0038 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 32 hom. )

Consequence

NEBL
NM_006393.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.102

Publications

22 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008779794).

BP6

Variant 10-20889923-C-G is Benign according to our data. Variant chr10-20889923-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45486.

BS2

High AC in GnomAd4 at 576 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEBL	NM_006393.3 link	c.180G>C	p.Lys60Asn	missense_variant	Exon 3 of 28	ENST00000377122.9	NP_006384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000377122.9 link	c.180G>C	p.Lys60Asn	missense_variant	Exon 3 of 28	1	NM_006393.3	ENSP00000366326.4

Frequencies

GnomAD3 genomes

AF:

0.00379

AC:

576

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00648

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00413

AC:

1030

AN:

249578

AF XY:

0.00429

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.0102

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00675

Gnomad OTH exome

AF:

0.00509

GnomAD4 exome

AF:

0.00567

AC:

8250

AN:

1454754

Hom.:

Cov.:

AF XY:

0.00562

AC XY:

4067

AN XY:

723810

show subpopulations

African (AFR)

AF:

0.000631

AC:

AN:

33280

American (AMR)

AF:

0.00205

AC:

AN:

44464

Ashkenazi Jewish (ASJ)

AF:

0.00880

AC:

229

AN:

26034

East Asian (EAS)

AF:

0.00

AC:

AN:

39596

South Asian (SAS)

AF:

0.00149

AC:

127

AN:

85206

European-Finnish (FIN)

AF:

0.000918

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00672

AC:

7440

AN:

1106870

Other (OTH)

AF:

0.00477

AC:

287

AN:

60174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

349

699

1048

1398

1747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

270

540

810

1080

1350

<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:

0.00378

AC:

576

AN:

152256

Hom.:

Cov.:

AF XY:

0.00349

AC XY:

260

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

41554

American (AMR)

AF:

0.00229

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00228

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000378

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00648

AC:

441

AN:

68008

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00627

Hom.:

Bravo

AF:

0.00393

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00710

AC:

ExAC

AF:

0.00385

AC:

467

EpiCase

AF:

0.00655

EpiControl

AF:

0.00611

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 04, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23299917, 21430528, 24082139, 27186169, 26321576, 25987543, 20951326, 27896284, 26383259) -

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEBL: BS1, BS2 -

Aug 01, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Based on the minor allele frequency in ExAC we consider this variant likely benign (seen in ~0.6% (423/66580) of European chromosomes). -

not specified

Benign:2

Apr 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 20, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Lys60Asn in exon 3 of NEBL: This variant is not expected to have clinical sign ificance because it has been identified in 0.6% (423/66580) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs41277374). -

Cardiovascular phenotype

Uncertain:1

Oct 04, 2013

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.K60N variant (also known as c.180G>C) is located in coding exon 3 of theNEBLgene. This alteration results from a G to C substitution at nucleotide position 180. The lysine at codon 60 is replaced by asparagine, an amino acid with some similar properties. Ã¢â‚¬â€¹Ã¢â‚¬â€¹In an initial publication associating NEBLwith dilated cardiomyopathy (DCM), this alteration was identified in a cohort of 260 individuals with DCM and absent in 600 control alleles. This alteration was found to be de novoin a proband with adult onset DCM. Authors subsequently developed a transgenic mouse model, and founder mice with this alteration developed severe heart failure at one year old. Embryos with this alteration did not survive, presenting the possibility of embryonic lethality with the p.K60N alteration(Purevjav E etal. J Am Coll Cardiol. 2010;56(18):1493-1502).However, a later publication denotes that the presence and frequency of this alteration in a large population based database from the Exome Sequencing Project (ESP) creates uncertainty regarding its pathogenicity (Andreasen C etal. Eur J Hum Genet. 2013;21(9):918-928). This variant was previously reported in dbSNP asrs41277374. Based on data from the NHLBI Exome Sequencing Project (ESP), the C-allele has an overall frequency of approximately0.52% (67/12998), having been observed in 0.71% (61/8594) of European American alleles, and in 0.14% (6/4404)of African American alleles studied. Based on data from the 1000 Genomes Project, the C-allele has an overall frequency of approximately0.18% (4/2184). The highest observed frequency was 1.12% (2/178) of Britishchromosomes studied. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively.Since supporting evidence for this variant is conflicting and limited at this time, its clinical significance remains unclear. -

NEBL-related disorder

Benign:1

Mar 27, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Primary dilated cardiomyopathy

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.075

T;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.065

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.84

T;D

M_CAP

Benign

0.043

MetaRNN

Benign

0.0088

T;T

MetaSVM

Benign

-0.59

MutationAssessor

Pathogenic

3.0

M;.

PhyloP100

0.10

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.9

D;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.0020

D;D

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.87

MutPred

0.50

Loss of methylation at K60 (P = 0.0203);.;

MVP

0.72

MPC

0.12

ClinPred

0.044

GERP RS

1.9

Varity_R

0.67

gMVP

0.41

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over