17-41755893-T-A

Position:

chr17-41755893-T-A

Variant summary

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

The NM_002230.4(JUP):c.2089A>T(p.Met697Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 1,605,478 control chromosomes in the GnomAD database, including 412,210 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 34334 hom., cov: 30)

Exomes 𝑓: 0.72 ( 377876 hom. )

Consequence

JUP
NM_002230.4 missense, splice_region

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19O:1

Conservation

PhyloP100: 1.03

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=1.7191055E-6).

BP6

Variant 17-41755893-T-A is Benign according to our data. Variant chr17-41755893-T-A is described in ClinVar as [Benign]. Clinvar id is 21304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41755893-T-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JUP	NM_002230.4 linkuse as main transcript	c.2089A>T	p.Met697Leu	missense_variant, splice_region_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.2089A>T	p.Met697Leu	missense_variant, splice_region_variant	14/14	1	NM_002230.4	ENSP00000377508	P1
JUP	ENST00000310706.9 linkuse as main transcript	c.2089A>T	p.Met697Leu	missense_variant, splice_region_variant	14/15	1		ENSP00000311113	P1
JUP	ENST00000393930.5 linkuse as main transcript	c.2089A>T	p.Met697Leu	missense_variant, splice_region_variant	14/15	5		ENSP00000377507	P1

Frequencies

GnomAD3 genomes

AF:

0.665

AC:

100923

AN:

151790

Hom.:

34303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.601

Gnomad AMI

AF:

0.817

Gnomad AMR

AF:

0.567

Gnomad ASJ

AF:

0.683

Gnomad EAS

AF:

0.345

Gnomad SAS

AF:

0.721

Gnomad FIN

AF:

0.648

Gnomad MID

AF:

0.737

Gnomad NFE

AF:

0.745

Gnomad OTH

AF:

0.665

GnomAD3 exomes

AF:

0.647

AC:

158651

AN:

245276

Hom.:

53640

AF XY:

0.664

AC XY:

88134

AN XY:

132744

show subpopulations

Gnomad AFR exome

AF:

0.598

Gnomad AMR exome

AF:

0.448

Gnomad ASJ exome

AF:

0.700

Gnomad EAS exome

AF:

0.337

Gnomad SAS exome

AF:

0.733

Gnomad FIN exome

AF:

0.653

Gnomad NFE exome

AF:

0.736

Gnomad OTH exome

AF:

0.671

GnomAD4 exome

AF:

0.716

AC:

1040678

AN:

1453570

Hom.:

377876

Cov.:

AF XY:

0.719

AC XY:

518649

AN XY:

721836

show subpopulations

Gnomad4 AFR exome

AF:

0.596

Gnomad4 AMR exome

AF:

0.466

Gnomad4 ASJ exome

AF:

0.695

Gnomad4 EAS exome

AF:

0.365

Gnomad4 SAS exome

AF:

0.732

Gnomad4 FIN exome

AF:

0.658

Gnomad4 NFE exome

AF:

0.745

Gnomad4 OTH exome

AF:

0.698

GnomAD4 genome

AF:

0.665

AC:

101012

AN:

151908

Hom.:

34334

Cov.:

AF XY:

0.659

AC XY:

48930

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.601

Gnomad4 AMR

AF:

0.567

Gnomad4 ASJ

AF:

0.683

Gnomad4 EAS

AF:

0.346

Gnomad4 SAS

AF:

0.722

Gnomad4 FIN

AF:

0.648

Gnomad4 NFE

AF:

0.745

Gnomad4 OTH

AF:

0.670

Alfa

AF:

0.709

Hom.:

6823

Bravo

AF:

0.649

TwinsUK

AF:

0.747

AC:

2769

ALSPAC

AF:

0.737

AC:

2842

ESP6500AA

AF:

0.615

AC:

2709

ESP6500EA

AF:

0.739

AC:

6356

ExAC

AF:

0.657

AC:

79707

Asia WGS

AF:

0.562

AC:

1954

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:10

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 01, 2011	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2011	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, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 16, 2016	- -

Arrhythmogenic right ventricular dysplasia 12

Benign:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	c.2089A>T) has been identified as cosegregating with a variant in desmoplakin. [Uzumcu et al 2006] -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

Naxos disease

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Cardiomyopathy

Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 23, 2022

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.69

DEOGEN2

Benign

0.16

T;T;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.46

.;.;T

MetaRNN

Benign

0.0000017

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.63

N;N;N

MutationTaster

Benign

0.82

P;P;P;P

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.080

N;N;N

REVEL

Benign

0.062

Sift

Benign

0.71

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.059

MutPred

0.17

Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);

MPC

0.45

ClinPred

0.0083

GERP RS

1.1

Varity_R

0.13

gMVP

0.30

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