rs41277374

Variant names:

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 45486.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3, Likely_benign=2}. Variant chr10-20889923-C-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 3 AR 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	O76041-1Q59FZ8

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		O76041-1

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

GnomAD3 exomes

AF:

0.00413

AC:

1030

AN:

249578

Hom.:

AF XY:

0.00429

AC XY:

578

AN XY:

134754

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 SAS exome

AF:

0.00144

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

Gnomad4 AFR exome

AF:

0.000631

Gnomad4 AMR exome

AF:

0.00205

Gnomad4 ASJ exome

AF:

0.00880

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00149

Gnomad4 FIN exome

AF:

0.000918

Gnomad4 NFE exome

AF:

0.00672

Gnomad4 OTH exome

AF:

0.00477

GnomAD4 genome

AF:

0.00378

AC:

576

AN:

152256

Hom.:

Cov.:

AF XY:

0.00349

AC XY:

260

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00229

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.000378

Gnomad4 NFE

AF:

0.00648

Gnomad4 OTH

AF:

0.00284

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

Likely benign, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Aug 01, 2016	Based on the minor allele frequency in ExAC we consider this variant likely benign (seen in ~0.6% (423/66580) of European chromosomes). -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	NEBL: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2020	This variant is associated with the following publications: (PMID: 23299917, 21430528, 24082139, 27186169, 26321576, 25987543, 20951326, 27896284, 26383259) -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 20, 2015	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). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2023	- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2013

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2019

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 02, 2025

- -

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

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;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over