chr17-41769029-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_002230.4(JUP):c.647G>A(p.Arg216Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,459,504 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 (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
JUP
NM_002230.4 missense
NM_002230.4 missense
Scores
6
5
8
Clinical Significance
Conservation
PhyloP100: 6.16
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 Uncertain_significance. Variant got 1 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.761
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| JUP | NM_002230.4 | c.647G>A | p.Arg216Gln | missense_variant | 4/14 | ENST00000393931.8 | NP_002221.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000820 AC: 2AN: 243950Hom.: 0 AF XY: 0.00000756 AC XY: 1AN XY: 132282
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GnomAD4 exome AF: 0.0000116 AC: 17AN: 1459504Hom.: 0 Cov.: 33 AF XY: 0.00000689 AC XY: 5AN XY: 725908
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GnomAD4 genome
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32
ExAC
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
| Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Oct 25, 2017 | Found in a Caucasian teenager with a new diagnosis of HCM and a long history of prolonged QTc intervals. He had a 130-gene Arrhythmia and Cardiomyopathy Comprehensive Panel with the Invitae laboratory. Results included 4 variants: -p.Arg187Leu (c.560G>T) in the DOLK gene -p.Leu691Phe (c.2071C>T) in the DSP gene -p.Gly1546Ser (c.4636G>A) in the FLNC gene -p.Arg216Gln (c.647G>A) in the JUP gene p.Arg216Gln (c.647G>A) in exon 4 of the JUP gene (NM_002230.2, ENST00000393931.7) Chromosome location 17:39925281 C / T Based on the information reviewed below, we classify this as a Variant of Uncertain Significance, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has not previously been reported in the literature in association with disease, according to the Invitae report. The JUP gene is associated with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) (MedGen UID: 409749) and autosomal recessive Naxos disease (MedGen UID: 321991). This is not consistent with our patient's clinical evaluation. This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a polar Glutamine. Arginine at this location is highly conserved across ~100 vertebrate species for which we have data. The adjacent residues are also well conserved. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In ExAC, Daniel MacArthur’s group from the Broad Institute has created a “constraint metric†for loss of function, indicating how tolerant each gene appears to be to heterozygous variants that lead to nonsense, splice acceptor, and splice donor variants that dramatically alter the protein. They call this pLI (Probability of LoF Intolerance). The closer the pLI is to 1, the more intolerant the gene appears to be. The pLI for the JUP gene is 0.04, meaning that it appears to be quite tolerant of heterozygous loss-of-function variants. However, of the variants in JUP that are listed in ClinVar as Likely Pathogenic or Pathogenic, approximately half are frameshift or nonsense variants (in the setting of recessive Naxos disease). This variant was reported in 2 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 2 non-Finnish European individuals (for the highest allele frequency: 0.002%), and overall MAF in gnomAD 0.001%. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.The curators made an effort to exclude individuals with severe pediatric diseases. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 16, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 25, 2022 | The p.R216Q variant (also known as c.647G>A), located in coding exon 3 of the JUP gene, results from a G to A substitution at nucleotide position 647. The arginine at codon 216 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Left ventricular noncompaction 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jun 03, 2019 | - - |
Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 28, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 216 of the JUP protein (p.Arg216Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with JUP-related conditions. ClinVar contains an entry for this variant (Variation ID: 536629). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;D;D;.;T;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;.;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;L;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D
REVEL
Benign
Sift
Benign
T;T;T;T;T;T;D
Sift4G
Benign
T;T;T;.;.;.;.
Polyphen
D;D;D;.;.;.;.
Vest4
MutPred
Gain of disorder (P = 0.1912);Gain of disorder (P = 0.1912);Gain of disorder (P = 0.1912);Gain of disorder (P = 0.1912);Gain of disorder (P = 0.1912);Gain of disorder (P = 0.1912);Gain of disorder (P = 0.1912);
MVP
MPC
0.14
ClinPred
D
GERP RS
Varity_R
gMVP
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