rs7405731

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002230.4(JUP):​c.213T>C​(p.Asp71Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.752 in 1,606,858 control chromosomes in the GnomAD database, including 458,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 45851 hom., cov: 32)
Exomes 𝑓: 0.75 ( 412516 hom. )

Consequence

JUP
NM_002230.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 0.455

Publications

22 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.66).
BP6
Variant 17-41769673-A-G is Benign according to our data. Variant chr17-41769673-A-G is described in ClinVar as [Benign]. Clinvar id is 45845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.455 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.875 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
JUPNM_002230.4 linkc.213T>C p.Asp71Asp synonymous_variant Exon 3 of 14 ENST00000393931.8 NP_002221.1 P14923A0A0S2Z487

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
JUPENST00000393931.8 linkc.213T>C p.Asp71Asp synonymous_variant Exon 3 of 14 1 NM_002230.4 ENSP00000377508.3 P14923

Frequencies

GnomAD3 genomes
AF:
0.771
AC:
117207
AN:
152052
Hom.:
45801
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.882
Gnomad AMI
AF:
0.752
Gnomad AMR
AF:
0.658
Gnomad ASJ
AF:
0.809
Gnomad EAS
AF:
0.517
Gnomad SAS
AF:
0.748
Gnomad FIN
AF:
0.670
Gnomad MID
AF:
0.829
Gnomad NFE
AF:
0.763
Gnomad OTH
AF:
0.763
GnomAD2 exomes
AF:
0.711
AC:
167306
AN:
235266
AF XY:
0.721
show subpopulations
Gnomad AFR exome
AF:
0.887
Gnomad AMR exome
AF:
0.523
Gnomad ASJ exome
AF:
0.826
Gnomad EAS exome
AF:
0.511
Gnomad FIN exome
AF:
0.681
Gnomad NFE exome
AF:
0.758
Gnomad OTH exome
AF:
0.734
GnomAD4 exome
AF:
0.750
AC:
1091432
AN:
1454688
Hom.:
412516
Cov.:
63
AF XY:
0.752
AC XY:
543348
AN XY:
722944
show subpopulations
African (AFR)
AF:
0.890
AC:
29779
AN:
33464
American (AMR)
AF:
0.538
AC:
23402
AN:
43516
Ashkenazi Jewish (ASJ)
AF:
0.816
AC:
21059
AN:
25804
East Asian (EAS)
AF:
0.518
AC:
20448
AN:
39484
South Asian (SAS)
AF:
0.759
AC:
64248
AN:
84700
European-Finnish (FIN)
AF:
0.684
AC:
35616
AN:
52044
Middle Eastern (MID)
AF:
0.805
AC:
4590
AN:
5700
European-Non Finnish (NFE)
AF:
0.763
AC:
846722
AN:
1109814
Other (OTH)
AF:
0.757
AC:
45568
AN:
60162
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.480
Heterozygous variant carriers
0
15408
30815
46223
61630
77038
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
20336
40672
61008
81344
101680
<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:
0.771
AC:
117318
AN:
152170
Hom.:
45851
Cov.:
32
AF XY:
0.762
AC XY:
56711
AN XY:
74376
show subpopulations
African (AFR)
AF:
0.882
AC:
36641
AN:
41536
American (AMR)
AF:
0.657
AC:
10050
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.809
AC:
2807
AN:
3468
East Asian (EAS)
AF:
0.517
AC:
2664
AN:
5150
South Asian (SAS)
AF:
0.750
AC:
3620
AN:
4828
European-Finnish (FIN)
AF:
0.670
AC:
7085
AN:
10582
Middle Eastern (MID)
AF:
0.820
AC:
241
AN:
294
European-Non Finnish (NFE)
AF:
0.763
AC:
51904
AN:
68000
Other (OTH)
AF:
0.767
AC:
1620
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.507
Heterozygous variant carriers
0
1377
2754
4131
5508
6885
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
856
1712
2568
3424
4280
<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:
0.754
Hom.:
27783
Bravo
AF:
0.770
Asia WGS
AF:
0.673
AC:
2346
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:8
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Clinical Genetics, Academic Medical Center
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

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Nov 30, 2011
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 08, 2025
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Naxos disease Benign:2
Jan 13, 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. -

Aug 19, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Arrhythmogenic right ventricular dysplasia 12 Benign:2
Jan 13, 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. -

Aug 19, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Mar 03, 2015
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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
BayesDel_noAF
Benign
-0.66
CADD
Benign
9.5
DANN
Benign
0.52
PhyloP100
0.46
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=94/6
polymorphism (auto)

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

Other links and lift over

dbSNP: rs7405731; hg19: chr17-39925925; COSMIC: COSV60277378; COSMIC: COSV60277378; API