rs1126821

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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

Publications

43 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: Benign. The variant received -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 VariationId is 21304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
JUP	NM_002230.4 link	c.2089A>T	p.Met697Leu	missense_variant, splice_region_variant	Exon 14 of 14	ENST00000393931.8	NP_002221.1	P14923A0A0S2Z487

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
JUP	ENST00000393931.8 link	c.2089A>T	p.Met697Leu	missense_variant, splice_region_variant	Exon 14 of 14	1	NM_002230.4	ENSP00000377508.3	P14923
JUP	ENST00000310706.9 link	c.2089A>T	p.Met697Leu	missense_variant, splice_region_variant	Exon 14 of 15	1		ENSP00000311113.5	P14923
JUP	ENST00000393930.5 link	c.2089A>T	p.Met697Leu	missense_variant, splice_region_variant	Exon 14 of 15	5		ENSP00000377507.1	P14923

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

GnomAD2 exomes

AF:

0.647

AC:

158651

AN:

245276

AF XY:

0.664

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 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

African (AFR)

AF:

0.596

AC:

19886

AN:

33342

American (AMR)

AF:

0.466

AC:

20611

AN:

44224

Ashkenazi Jewish (ASJ)

AF:

0.695

AC:

17960

AN:

25850

East Asian (EAS)

AF:

0.365

AC:

14393

AN:

39482

South Asian (SAS)

AF:

0.732

AC:

62789

AN:

85720

European-Finnish (FIN)

AF:

0.658

AC:

34440

AN:

52346

Middle Eastern (MID)

AF:

0.714

AC:

4089

AN:

5730

European-Non Finnish (NFE)

AF:

0.745

AC:

824565

AN:

1106796

Other (OTH)

AF:

0.698

AC:

41945

AN:

60080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

15308

30616

45924

61232

76540

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20024

40048

60072

80096

100120

<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:

0.665

AC:

101012

AN:

151908

Hom.:

34334

Cov.:

AF XY:

0.659

AC XY:

48930

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.601

AC:

24901

AN:

41414

American (AMR)

AF:

0.567

AC:

8656

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.683

AC:

2370

AN:

3472

East Asian (EAS)

AF:

0.346

AC:

1764

AN:

5104

South Asian (SAS)

AF:

0.722

AC:

3474

AN:

4814

European-Finnish (FIN)

AF:

0.648

AC:

6854

AN:

10584

Middle Eastern (MID)

AF:

0.728

AC:

214

AN:

294

European-Non Finnish (NFE)

AF:

0.745

AC:

50623

AN:

67934

Other (OTH)

AF:

0.670

AC:

1414

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1655

3310

4964

6619

8274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

804

1608

2412

3216

4020

<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:

0.709

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

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 16, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 08, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 01, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Arrhythmogenic right ventricular dysplasia 12

Benign:2Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

c.2089A>T) has been identified as cosegregating with a variant in desmoplakin. [Uzumcu et al 2006] -

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Naxos disease

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cardiomyopathy

Benign:1

Sep 23, 2022

Cohesion Phenomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 09, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

1.0

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

Mutation Taster

=99/1

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over