rs1166698

Variant names:

Variant summary

Our verdict is Benign. The variant received -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:10

Conservation

PhyloP100: 9.36

Publications

45 publications found

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 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy 1CC
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
hypertrophic cardiomyopathy 20
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

NEXN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 47911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
NEXN	NM_144573.4 link	c.733G>A	p.Gly245Arg	missense_variant	Exon 8 of 13	ENST00000334785.12	NP_653174.3	Q0ZGT2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12 link	c.733G>A	p.Gly245Arg	missense_variant	Exon 8 of 13	1	NM_144573.4	ENSP00000333938.7		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

GnomAD2 exomes

AF:

0.182

AC:

45443

AN:

249110

AF XY:

0.180

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 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

African (AFR)

AF:

0.0341

AC:

1140

AN:

33440

American (AMR)

AF:

0.141

AC:

6304

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.215

AC:

5610

AN:

26126

East Asian (EAS)

AF:

0.399

AC:

15837

AN:

39656

South Asian (SAS)

AF:

0.0759

AC:

6540

AN:

86164

European-Finnish (FIN)

AF:

0.167

AC:

8941

AN:

53412

Middle Eastern (MID)

AF:

0.171

AC:

987

AN:

5764

European-Non Finnish (NFE)

AF:

0.211

AC:

234847

AN:

1111834

Other (OTH)

AF:

0.192

AC:

11581

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

12418

24836

37255

49673

62091

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8090

16180

24270

32360

40450

<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:

0.155

AC:

23565

AN:

151918

Hom.:

2404

Cov.:

AF XY:

0.151

AC XY:

11235

AN XY:

74214

show subpopulations

African (AFR)

AF:

0.0388

AC:

1610

AN:

41454

American (AMR)

AF:

0.142

AC:

2169

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.213

AC:

739

AN:

3470

East Asian (EAS)

AF:

0.402

AC:

2076

AN:

5158

South Asian (SAS)

AF:

0.0750

AC:

361

AN:

4812

European-Finnish (FIN)

AF:

0.162

AC:

1705

AN:

10520

Middle Eastern (MID)

AF:

0.170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.211

AC:

14303

AN:

67928

Other (OTH)

AF:

0.150

AC:

317

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

964

1928

2893

3857

4821

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

266

532

798

1064

1330

<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:

0.198

Hom.:

13638

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 18, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 24, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cardiovascular phenotype

Benign:1

Mar 11, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 03, 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

0.29

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

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

MutationAssessor

Pathogenic

3.4

.;.;M;.

PhyloP100

9.4

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

Mutation Taster

=89/11

polymorphism (auto)

(source)

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

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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