rs41283425

chr17-41769461-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R142C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.039 (128 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2047 hom.)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 7.90

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]

ACMG classification

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/exons	MANE	UniProt
JUP	NM_002230.4	c.425G>A	p.Arg142His	missense_variant	3/14	ENST00000393931.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JUP	ENST00000393931.8	c.425G>A	p.Arg142His	missense_variant	3/14	1	NM_002230.4	P1

Frequencies

GnomAD3 genomes AF: 0.0393 AC: 5973 AN: 152102 Hom.: 130 Cov.: 32

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

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.: 33 AF XY: 0.0503 AC XY: 36564 AN XY: 726432

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.: 32 AF XY: 0.0383 AC XY: 2854 AN XY: 74434

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: 49

ESP6500EA AF: 0.0581 AC: 500

ExAC AF: 0.0440 AC: 5347

Asia WGS AF: 0.0170 AC: 59 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:10

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 17, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 16, 2011	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 29, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Arrhythmogenic right ventricular dysplasia 12 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Naxos disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 23, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

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

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 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. -

Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 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	Uncertain	0.56
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	32
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	D
MetaRNN	Benign	0.0089	T;T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	M;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
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	T
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

Other links and lift over

dbSNP: rs41283425; hg19: chr17-39925713;