rs782284038

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BP6

The NM_002230.4(JUP):c.509C>T(p.Ser170Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000879 in 1,603,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S170W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

JUP
NM_002230.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 9.99

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 Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.833

BP6

Variant 17-41769167-G-A is Benign according to our data. Variant chr17-41769167-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201812.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JUP	NM_002230.4 linkuse as main transcript	c.509C>T	p.Ser170Leu	missense_variant	4/14	ENST00000393931.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JUP	ENST00000393931.8 linkuse as main transcript	c.509C>T	p.Ser170Leu	missense_variant	4/14	1	NM_002230.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000456

AC:

AN:

241372

Hom.:

AF XY:

0.0000305

AC XY:

AN XY:

131180

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000716

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000937

AC:

136

AN:

1451752

Hom.:

Cov.:

AF XY:

0.0000817

AC XY:

AN XY:

722458

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

JUP-related condition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 06, 2023

The JUP c.509C>T variant is predicted to result in the amino acid substitution p.Ser170Leu. This variant was reported in an individual with dilated cardiomyopathy (Table S3, Mazzarotto et al. 2020. PubMed ID: 31983221). This variant is reported in 0.0063% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-39925419-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Naxos disease

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 23, 2018

A variant of uncertain significance has been identified in the JUP gene. The S170L variant has not been published as pathogenic or been reported as benign to our knowledge. It has been observed in one other individual referred for arrhythmia genetic testing at GeneDx, although this individual harbored additional cardiogenetic variants and no segregation data are available. This variant is also observed at a global allele frequency of 11/267372 (0.004%) alleles in large population cohorts, including 7/124788 (0.006%) alleles from individuals of European (non-Finnish) ancestry (Lek et al., 2016). The S170L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. -

Arrhythmogenic right ventricular dysplasia 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 170 of the JUP protein (p.Ser170Leu). This variant is present in population databases (rs794729034, gnomAD 0.006%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 201812). 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 disruptive. 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 16, 2019

Variant summary: JUP c.509C>T (p.Ser170Leu) results in a non-conservative amino acid change located in the Armadillo domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 241372 control chromosomes. The observed variant frequency is approximately 4.5 fold the estimated maximal allele frequency expected for a pathogenic variant in JUP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.509C>T in individuals affected with Arrhythmia and no experimental evidence demonstrating an impact on protein function have been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 08, 2023

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Uncertain

0.040

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

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

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.83

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

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

2.0

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.0

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

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.77

MutPred

0.62

Loss of disorder (P = 0.0292);Loss of disorder (P = 0.0292);Loss of disorder (P = 0.0292);Loss of disorder (P = 0.0292);Loss of disorder (P = 0.0292);Loss of disorder (P = 0.0292);Loss of disorder (P = 0.0292);

MVP

0.90

MPC

0.34

ClinPred

0.88

GERP RS

5.8

Varity_R

0.66

gMVP

0.60

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