rs1166698

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_144573.4(NEXN):c.733G>A(p.Gly245Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,344 control chromosomes in the GnomAD database, including 33,815 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2404 hom., cov: 32)

Exomes 𝑓: 0.20 ( 31411 hom. )

Consequence

NEXN
NM_144573.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 9.36

Variant links:

Genes affected

NEXN (HGNC:29557): (nexilin F-actin binding protein) This gene encodes a filamentous actin-binding protein that may function in cell adhesion and migration. Mutations in this gene have been associated with dilated cardiomyopathy, also known as CMD1CC. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2010]

NEXN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018042922).

BP6

Variant 1-77926761-G-A is Benign according to our data. Variant chr1-77926761-G-A is described in ClinVar as [Benign]. Clinvar id is 47911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-77926761-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEXN	NM_144573.4 linkuse as main transcript	c.733G>A	p.Gly245Arg	missense_variant	8/13	ENST00000334785.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEXN	ENST00000334785.12 linkuse as main transcript	c.733G>A	p.Gly245Arg	missense_variant	8/13	1	NM_144573.4	P3	Q0ZGT2-1

Frequencies

GnomAD3 genomes

AF:

0.155

AC:

23573

AN:

151800

Hom.:

2405

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0390

Gnomad AMI

AF:

0.258

Gnomad AMR

AF:

0.142

Gnomad ASJ

AF:

0.213

Gnomad EAS

AF:

0.403

Gnomad SAS

AF:

0.0743

Gnomad FIN

AF:

0.162

Gnomad MID

AF:

0.174

Gnomad NFE

AF:

0.211

Gnomad OTH

AF:

0.152

GnomAD3 exomes

AF:

0.182

AC:

45443

AN:

249110

Hom.:

4966

AF XY:

0.180

AC XY:

24383

AN XY:

135180

show subpopulations

Gnomad AFR exome

AF:

0.0338

Gnomad AMR exome

AF:

0.141

Gnomad ASJ exome

AF:

0.217

Gnomad EAS exome

AF:

0.392

Gnomad SAS exome

AF:

0.0777

Gnomad FIN exome

AF:

0.163

Gnomad NFE exome

AF:

0.211

Gnomad OTH exome

AF:

0.184

GnomAD4 exome

AF:

0.200

AC:

291787

AN:

1461426

Hom.:

31411

Cov.:

AF XY:

0.196

AC XY:

142843

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.0341

Gnomad4 AMR exome

AF:

0.141

Gnomad4 ASJ exome

AF:

0.215

Gnomad4 EAS exome

AF:

0.399

Gnomad4 SAS exome

AF:

0.0759

Gnomad4 FIN exome

AF:

0.167

Gnomad4 NFE exome

AF:

0.211

Gnomad4 OTH exome

AF:

0.192

GnomAD4 genome

AF:

0.155

AC:

23565

AN:

151918

Hom.:

2404

Cov.:

AF XY:

0.151

AC XY:

11235

AN XY:

74214

show subpopulations

Gnomad4 AFR

AF:

0.0388

Gnomad4 AMR

AF:

0.142

Gnomad4 ASJ

AF:

0.213

Gnomad4 EAS

AF:

0.402

Gnomad4 SAS

AF:

0.0750

Gnomad4 FIN

AF:

0.162

Gnomad4 NFE

AF:

0.211

Gnomad4 OTH

AF:

0.150

Alfa

AF:

0.201

Hom.:

6602

Bravo

AF:

0.153

TwinsUK

AF:

0.212

AC:

786

ALSPAC

AF:

0.207

AC:

796

ESP6500AA

AF:

0.0466

AC:

169

ESP6500EA

AF:

0.207

AC:

1690

ExAC

AF:

0.184

AC:

22241

Asia WGS

AF:

0.187

AC:

649

AN:

3476

EpiCase

AF:

0.215

EpiControl

AF:

0.215

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 24, 2011	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.12

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.21

T;.;T;T

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;D;D;T

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-0.29

MutationTaster

Benign

5.5e-9

P;P;P

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Uncertain

0.37

Sift

Uncertain

0.025

D;D;D;D

Sift4G

Benign

0.23

T;T;T;T

Polyphen

1.0

.;.;D;.

Vest4

0.46, 0.24

MutPred

0.10

.;.;Gain of solvent accessibility (P = 0.0014);.;

MPC

0.35

ClinPred

0.046

GERP RS

5.6

Varity_R

0.13

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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