rs147628503

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_002230.4(JUP):c.2069A>G(p.Asn690Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,613,856 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

JUP
NM_002230.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:2

Conservation

PhyloP100: 1.91

Publications

7 publications found

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 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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.112629175).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000177 (27/152180) while in subpopulation NFE AF = 0.000338 (23/68028). AF 95% confidence interval is 0.00023. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.2069A>G	p.Asn690Ser	missense	Exon 13 of 14	NP_002221.1	P14923
JUP	NM_001352773.2		c.2069A>G	p.Asn690Ser	missense	Exon 13 of 14	NP_001339702.1	P14923
JUP	NM_001352774.2		c.2069A>G	p.Asn690Ser	missense	Exon 13 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.2069A>G	p.Asn690Ser	missense	Exon 13 of 14	ENSP00000377508.3	P14923
JUP	ENST00000310706.9	TSL:1	c.2069A>G	p.Asn690Ser	missense	Exon 13 of 15	ENSP00000311113.5	P14923
JUP	ENST00000393930.5	TSL:5	c.2069A>G	p.Asn690Ser	missense	Exon 13 of 15	ENSP00000377507.1	P14923

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000338

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000996

AC:

AN:

251026

AF XY:

0.000125

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 FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000190

AC:

277

AN:

1461676

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

131

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.0000671

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.000233

AC:

259

AN:

1111958

Other (OTH)

AF:

0.0000994

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000177

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41442

American (AMR)

AF:

0.000196

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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:

0.000245

Hom.:

Bravo

AF:

0.000140

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000119

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 (2)

Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 (2)

not specified (2)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Naxos disease (1)

not provided (1)

Ventricular fibrillation, paroxysmal familial, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.21

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.78

M_CAP

Benign

0.021

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

1.9

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.43

REVEL

Benign

0.11

Sift

Benign

0.55

Sift4G

Benign

0.44

Polyphen

0.088

Vest4

0.24

MVP

0.67

MPC

0.38

ClinPred

0.076

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.027

gMVP

0.31

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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