chr17-41769043-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_002230.4(JUP):c.633C>A(p.Asn211Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,756 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 Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N211H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

JUP
NM_002230.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:2

Conservation

PhyloP100: 4.25

Publications

0 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 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, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JUP	NM_002230.4 link	c.633C>A	p.Asn211Lys	missense_variant	Exon 4 of 14	ENST00000393931.8	NP_002221.1	P14923A0A0S2Z487

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8 link	c.633C>A	p.Asn211Lys	missense_variant	Exon 4 of 14	1	NM_002230.4	ENSP00000377508.3		P14923

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000810

AC:

AN:

246866

AF XY:

0.0000149

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460756

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726634

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53002

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111672

Other (OTH)

AF:

0.00

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000595

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.0078

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

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

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.97

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

M_CAP

Benign

0.015

MetaRNN

Pathogenic

0.77

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

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.6

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

PhyloP100

4.3

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.1

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

REVEL

Uncertain

0.38

Sift

Benign

0.043

D;D;D;D;D;T;T

Sift4G

Benign

0.070

T;T;T;.;.;.;.

Polyphen

0.98

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

Vest4

0.91

MutPred

0.76

Gain of ubiquitination at N211 (P = 0.0428);Gain of ubiquitination at N211 (P = 0.0428);Gain of ubiquitination at N211 (P = 0.0428);Gain of ubiquitination at N211 (P = 0.0428);Gain of ubiquitination at N211 (P = 0.0428);Gain of ubiquitination at N211 (P = 0.0428);Gain of ubiquitination at N211 (P = 0.0428);

MVP

0.81

MPC

0.22

ClinPred

0.96

GERP RS

4.8

Varity_R

0.57

gMVP

0.63

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over