NM_002230.4:c.425G>A

Variant names:

Variant summary

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

The NM_002230.4(JUP):c.425G>A(p.Arg142His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0487 in 1,612,690 control chromosomes in the GnomAD database, including 2,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R142R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.039 ( 128 hom., cov: 32)

Exomes 𝑓: 0.050 ( 2047 hom. )

Consequence

JUP
NM_002230.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 7.90

Variant links:

Genes affected

JUP (HGNC:6207): (junction plakoglobin) This gene encodes a major cytoplasmic protein which is the only known constituent common to submembranous plaques of both desmosomes and intermediate junctions. This protein forms distinct complexes with cadherins and desmosomal cadherins and is a member of the catenin family since it contains a distinct repeating amino acid motif called the armadillo repeat. Mutation in this gene has been associated with Naxos disease. Alternative splicing occurs in this gene; however, not all transcripts have been fully described. [provided by RefSeq, Jul 2008]

JUP 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=0.00889793).

BP6

Variant 17-41769461-C-T is Benign according to our data. Variant chr17-41769461-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 45851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41769461-C-T is described in Lovd as [Benign]. Variant chr17-41769461-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JUP	NM_002230.4 link	c.425G>A	p.Arg142His	missense_variant	Exon 3 of 14	ENST00000393931.8	NP_002221.1	P14923A0A0S2Z487

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8 link	c.425G>A	p.Arg142His	missense_variant	Exon 3 of 14	1	NM_002230.4	ENSP00000377508.3		P14923

Frequencies

GnomAD3 genomes

AF:

0.0393

AC:

5973

AN:

152102

Hom.:

130

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00797

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0343

Gnomad ASJ

AF:

0.0669

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0332

Gnomad FIN

AF:

0.0558

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0589

Gnomad OTH

AF:

0.0416

GnomAD3 exomes

AF:

0.0437

AC:

10768

AN:

246352

Hom.:

318

AF XY:

0.0469

AC XY:

6268

AN XY:

133660

show subpopulations

Gnomad AFR exome

AF:

0.00754

Gnomad AMR exome

AF:

0.0267

Gnomad ASJ exome

AF:

0.0662

Gnomad EAS exome

AF:

0.000385

Gnomad SAS exome

AF:

0.0431

Gnomad FIN exome

AF:

0.0566

Gnomad NFE exome

AF:

0.0563

Gnomad OTH exome

AF:

0.0553

GnomAD4 exome

AF:

0.0497

AC:

72625

AN:

1460470

Hom.:

2047

Cov.:

AF XY:

0.0503

AC XY:

36564

AN XY:

726432

show subpopulations

Gnomad4 AFR exome

AF:

0.00777

Gnomad4 AMR exome

AF:

0.0277

Gnomad4 ASJ exome

AF:

0.0639

Gnomad4 EAS exome

AF:

0.000328

Gnomad4 SAS exome

AF:

0.0452

Gnomad4 FIN exome

AF:

0.0598

Gnomad4 NFE exome

AF:

0.0529

Gnomad4 OTH exome

AF:

0.0506

GnomAD4 genome

AF:

0.0392

AC:

5966

AN:

152220

Hom.:

128

Cov.:

AF XY:

0.0383

AC XY:

2854

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00794

Gnomad4 AMR

AF:

0.0341

Gnomad4 ASJ

AF:

0.0669

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0326

Gnomad4 FIN

AF:

0.0558

Gnomad4 NFE

AF:

0.0589

Gnomad4 OTH

AF:

0.0412

Alfa

AF:

0.0553

Hom.:

394

Bravo

AF:

0.0369

TwinsUK

AF:

0.0556

AC:

206

ALSPAC

AF:

0.0488

AC:

188

ESP6500AA

AF:

0.0111

AC:

ESP6500EA

AF:

0.0581

AC:

500

ExAC

AF:

0.0440

AC:

5347

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:10

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

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 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 17, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 29, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 16, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 12

Benign:2

Aug 01, 2017

Phosphorus, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25445213, 19863551) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Naxos disease

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiomyopathy

Benign:1

Sep 23, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 27, 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. -

Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12

Benign:1

Feb 04, 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

Uncertain

0.56

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

D;D;D;.;T;.;T

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

.;.;D;D;D;D;D

MetaRNN

Benign

0.0089

T;T;T;T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.9

M;M;M;.;.;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-4.0

D;D;D;D;D;D;D

REVEL

Uncertain

0.50

Sift

Uncertain

0.0060

D;D;D;D;D;D;D

Sift4G

Uncertain

0.018

D;D;D;.;.;.;.

Polyphen

1.0

D;D;D;.;.;.;.

Vest4

0.26

MPC

0.46

ClinPred

0.014

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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