rs375451560
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7
The NM_002230.4(JUP):c.1959C>T(p.Ser653=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000088 ( 0 hom. )
Consequence
JUP
NM_002230.4 synonymous
NM_002230.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.76
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
BP6
Variant 17-41757502-G-A is Benign according to our data. Variant chr17-41757502-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178040.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1}. Variant chr17-41757502-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-2.76 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JUP | NM_002230.4 | c.1959C>T | p.Ser653= | synonymous_variant | 12/14 | ENST00000393931.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JUP | ENST00000393931.8 | c.1959C>T | p.Ser653= | synonymous_variant | 12/14 | 1 | NM_002230.4 | P1 | |
JUP | ENST00000310706.9 | c.1959C>T | p.Ser653= | synonymous_variant | 12/15 | 1 | P1 | ||
JUP | ENST00000393930.5 | c.1959C>T | p.Ser653= | synonymous_variant | 12/15 | 5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152196Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000835 AC: 21AN: 251482Hom.: 0 AF XY: 0.0000956 AC XY: 13AN XY: 135920
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GnomAD4 exome AF: 0.0000882 AC: 129AN: 1461882Hom.: 0 Cov.: 38 AF XY: 0.0000976 AC XY: 71AN XY: 727244
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GnomAD4 genome AF: 0.000112 AC: 17AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74340
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:9
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2012 | Ser653Ser in exon 12 of JUP: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 1/7020 European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS). Ser653Ser in exon 12 of JUP (allele frequency = 1/7020) ** - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 02, 2019 | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Naxos disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
JUP-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 30, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 15, 2021 | - - |
Arrhythmogenic right ventricular dysplasia 12 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 07, 2017 | This alteration is classified as likely 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
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2024 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at