Genetic Variant JUP:p.Val603Leu (chr17-41757751-C-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002230.4(JUP):c.1807G>T(p.Val603Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,612,190 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign 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. V603M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 2 hom. )

Consequence

JUP
NM_002230.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 7.78

Publications

12 publications found

Variant links:

COSMIC-nc: COSV100159348

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 Gene-Disease associations (from GenCC):

arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
arrhythmogenic right ventricular dysplasia 12
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
inherited epidermolysis bullosa
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
Naxos disease
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet
lethal acantholytic epidermolysis bullosa
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

JUP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.043173373).

BP6

Variant 17-41757751-C-A is Benign according to our data. Variant chr17-41757751-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180376.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000322 (49/152268) while in subpopulation EAS AF = 0.00617 (32/5186). AF 95% confidence interval is 0.00449. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002230.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
JUP	NM_002230.4	MANE Select	c.1807G>T	p.Val603Leu	missense	Exon 11 of 14	NP_002221.1	P14923
JUP	NM_001352773.2		c.1807G>T	p.Val603Leu	missense	Exon 11 of 14	NP_001339702.1	P14923
JUP	NM_001352774.2		c.1807G>T	p.Val603Leu	missense	Exon 11 of 15	NP_001339703.1	P14923

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
JUP	ENST00000393931.8	TSL:1 MANE Select	c.1807G>T	p.Val603Leu	missense	Exon 11 of 14	ENSP00000377508.3	P14923
JUP	ENST00000310706.9	TSL:1	c.1807G>T	p.Val603Leu	missense	Exon 11 of 15	ENSP00000311113.5	P14923
JUP	ENST00000393930.5	TSL:5	c.1807G>T	p.Val603Leu	missense	Exon 11 of 15	ENSP00000377507.1	P14923

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152150

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:

0.00616

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000672

AC:

166

AN:

246946

AF XY:

0.000732

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00562

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000209

AC:

305

AN:

1459922

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

191

AN XY:

726058

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26012

East Asian (EAS)

AF:

0.00285

AC:

113

AN:

39670

South Asian (SAS)

AF:

0.00191

AC:

164

AN:

86032

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110962

Other (OTH)

AF:

0.000464

AC:

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000322

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41550

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00617

AC:

AN:

5186

South Asian (SAS)

AF:

0.00352

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.000272

ExAC

AF:

0.000626

AC:

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Arrhythmogenic right ventricular dysplasia 12 (1)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

JUP-related disorder (1)

Naxos disease (1)

Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 (1)

not provided (1)

not specified (1)

Ventricular fibrillation, paroxysmal familial, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.084

MetaRNN

Benign

0.043

MetaSVM

Uncertain

-0.066

MutationAssessor

Uncertain

2.3

PhyloP100

7.8

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.57

Sift

Benign

0.050

Sift4G

Benign

0.067

Polyphen

1.0

Vest4

0.96

MutPred

0.67

Gain of helix (P = 0.132)

MVP

0.88

MPC

0.55

ClinPred

0.11

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.55

gMVP

0.61

Mutation Taster

=4/96

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over