10-20889861-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006393.3(NEBL):c.242G>C(p.Gly81Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000683 in 1,610,152 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G81C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

NEBL
NM_006393.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.65

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0644359).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEBL	NM_006393.3 linkuse as main transcript	c.242G>C	p.Gly81Ala	missense_variant	3/28	ENST00000377122.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEBL	ENST00000377122.9 linkuse as main transcript	c.242G>C	p.Gly81Ala	missense_variant	3/28	1	NM_006393.3		O76041-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000686

AC:

AN:

1458078

Hom.:

Cov.:

AF XY:

0.00000965

AC XY:

AN XY:

725636

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000812

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 05, 2017

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a NEBL-related disease. This sequence change replaces glycine with alanine at codon 81 of the NEBL protein (p.Gly81Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.0032

T;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.0030

MetaRNN

Benign

0.064

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

0.76

D;D;N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.50

N;N

REVEL

Benign

0.11

Sift

Benign

0.54

T;T

Sift4G

Benign

0.17

T;.

Polyphen

0.0010

B;.

Vest4

0.35

MutPred

0.41

Loss of helix (P = 0.0558);.;

MVP

0.31

MPC

0.016

ClinPred

0.18

GERP RS

6.2

Varity_R

0.091

gMVP

0.34

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