17-41755877-C-T

Position:

chr17-41755877-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000393931.8(JUP):c.2105G>A(p.Arg702His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,609,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R702C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

JUP
ENST00000393931.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 3.44

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1477339).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JUP	NM_002230.4 linkuse as main transcript	c.2105G>A	p.Arg702His	missense_variant	14/14	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
JUP	ENST00000393931.8 linkuse as main transcript	c.2105G>A	p.Arg702His	missense_variant	14/14	1	NM_002230.4	ENSP00000377508	P1
JUP	ENST00000310706.9 linkuse as main transcript	c.2105G>A	p.Arg702His	missense_variant	14/15	1		ENSP00000311113	P1
JUP	ENST00000393930.5 linkuse as main transcript	c.2105G>A	p.Arg702His	missense_variant	14/15	5		ENSP00000377507	P1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152008

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000568

AC:

AN:

246582

Hom.:

AF XY:

0.0000600

AC XY:

AN XY:

133366

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000117

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000370

AC:

AN:

1457506

Hom.:

Cov.:

AF XY:

0.0000428

AC XY:

AN XY:

724430

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.0000433

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152008

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74228

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2019	Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 178849; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23861362) -

Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 702 of the JUP protein (p.Arg702His). This variant is present in population databases (rs200690479, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with JUP-related conditions. ClinVar contains an entry for this variant (Variation ID: 178849). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 20, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 16, 2015

The p.Arg702His variant in JUP has been identified by our laboratory in 1 Caucas ian individual with CPVT. However, this individual carried a pathogenic variant in RYR2, and the p.Arg702His variant was also found in an apparently unaffected member of the same family. This variant has also been identified in 8/66036 Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs200690479). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg702His variant is uncertain. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 16, 2023

- -

Left ventricular noncompaction

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Apr 04, 2017

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2016

The p.R702H variant (also known as c.2105G>A), located in coding exon 13 of the JUP gene, results from a G to A substitution at nucleotide position 2105. The arginine at codon 702 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This variant was previously reported in the SNPDatabase as rs200690479. Based on data from ExAC, the A allele has an overall frequency of <0.01% (6/104582). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T;T

Eigen

Benign

-0.14

Eigen_PC

Benign

0.078

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.78

.;.;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;L;L

MutationTaster

Benign

0.95

D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.42

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.046

D;D;D

Sift4G

Benign

0.14

T;T;T

Polyphen

0.0030

B;B;B

Vest4

0.36

MutPred

0.26

Gain of catalytic residue at M704 (P = 0.0578);Gain of catalytic residue at M704 (P = 0.0578);Gain of catalytic residue at M704 (P = 0.0578);

MVP

0.69

MPC

0.61

ClinPred

0.13

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.097

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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