rs146275785

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_006393.3(NEBL):c.1775C>T(p.Ala592Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000365 in 1,561,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A592E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

NEBL
NM_006393.3 missense, splice_region

Scores

Splicing: ADA: 0.0002578

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.495

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 -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05102563).

BP6

Variant 10-20828531-G-A is Benign according to our data. Variant chr10-20828531-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 379214.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr10-20828531-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEBL	NM_006393.3 linkuse as main transcript	c.1775C>T	p.Ala592Val	missense_variant, splice_region_variant	17/28	ENST00000377122.9	NP_006384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000377122.9 linkuse as main transcript	c.1775C>T	p.Ala592Val	missense_variant, splice_region_variant	17/28	1	NM_006393.3	ENSP00000366326		O76041-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152108

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000720

AC:

AN:

249848

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135080

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.0000996

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.0000620

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000355

AC:

AN:

1408922

Hom.:

Cov.:

AF XY:

0.0000341

AC XY:

AN XY:

703974

show subpopulations

Gnomad4 AFR exome

AF:

0.0000621

Gnomad4 AMR exome

AF:

0.000180

Gnomad4 ASJ exome

AF:

0.0000387

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.0000319

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74294

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:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000110

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 27, 2021

This sequence change replaces alanine with valine at codon 592 of the NEBL protein (p.Ala592Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs146275785, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with NEBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 379214). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 20, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.83

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.015

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.040

M_CAP

Benign

0.0031

MetaRNN

Benign

0.051

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

-1.9

REVEL

Benign

0.034

Sift

Benign

0.077

Sift4G

Uncertain

0.055

Polyphen

0.0

Vest4

0.17

MutPred

0.42

Loss of ubiquitination at K597 (P = 0.0638);

MVP

0.16

MPC

0.016

ClinPred

0.026

GERP RS

-2.5

Varity_R

0.045

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00026

dbscSNV1_RF

Benign

0.16

SpliceAI score (max)

0.010

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