rs542745694
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS1
The NM_002230.4(JUP):c.266T>C(p.Met89Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,605,972 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
JUP
NM_002230.4 missense
NM_002230.4 missense
Scores
4
11
4
Clinical Significance
Conservation
PhyloP100: 9.32
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 -5 ACMG points.
BP6
Variant 17-41769620-A-G is Benign according to our data. Variant chr17-41769620-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 583093.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
BS1
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000103 (15/1453648) while in subpopulation AMR AF= 0.000279 (12/42972). AF 95% confidence interval is 0.00016. There are 0 homozygotes in gnomad4_exome. There are 6 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| JUP | NM_002230.4 | c.266T>C | p.Met89Thr | missense_variant | 3/14 | ENST00000393931.8 | NP_002221.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| JUP | ENST00000393931.8 | c.266T>C | p.Met89Thr | missense_variant | 3/14 | 1 | NM_002230.4 | ENSP00000377508.3 |
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152206Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000559 AC: 13AN: 232480Hom.: 0 AF XY: 0.0000239 AC XY: 3AN XY: 125424
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1453648Hom.: 0 Cov.: 34 AF XY: 0.00000831 AC XY: 6AN XY: 722282
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GnomAD4 genome 0.0000263 AC: 4AN: 152324Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74486
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
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 | Apr 21, 2017 | This patient has a diagnosis of HCM and had a Comprehensive Cardiomyopathy Panel with the GeneDx laboratory. The test included sequencing of 76 genes and additional deletion/duplication analysis of 60 of those genes (nuclear genes) associated with various forms of cardiomyopathy: ABCC9, ACTC (ACTC1), ACTN2, ANKRD1, BAG3 , BRAF, CAV3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL , NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. 7 variants were reported. We believe the MYH7 variant is the most likely to be pathogenic: • p.Ala868Pro (A868P; c.2602G>C) in the MYH7 gene • p.Leu327Val (L327V; c.979C>G) in the PRKAG2 gene • p.Pro323Thr (P323T; c.967C>A) in the GLA gene • p.Ala749Ile (A749I; c.2245_2246delGCinsAT) in the PKP2 gene • p.Met89Thr (M89T; c.266T>C) in the JUP gene • p.Asp2771Ala (D2771A; c.8312A>C) in the DMD gene • Duplication of at least exons 1-2 of the LAMA4 gene Given the large number of genes included on this panel, and the large and variable nature of some of these genes, it is expected that most individuals (including individuals who don't have inherited cardiac disease) would have at least one and possibly several rare variants found with this test. As a result, it is important to consider the data available on each variant to determine whether it is a disease-predisposing variant or one of the many benign rare variants that we all have in our DNA. p.Met89Thr (M89T; c.266T>C) in exon 3 of the JUP gene (NM_002230.2; ENST00000393931.7) Chromosome position: 17:39925872 A / G Based on the information reviewed below, including lack of case data, we classify it as a Variant of Uncertain Signficance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. Because of its increased prevalence among individuals with Latino ancestry (like our patient), we suspect that it is more likely to be benign. Of note, the JUP gene is associated with ARVC, which is not our patient’s phenotype. This variant has not been reported in the literature in association with disease. This is a nonconservative amino acid change, resulting in the replacement of a nonpolar Methionine with a polar Threonine. Methionine at this location is highly conserved across vertebrate species, although it is replaced by another nonpolar amino acid in a few species. There are no missense variants within 10 residues currently listed as Pathogenic or Likely Pathogenic in ClinVar, which suggests this region of the protein may be tolerant of change. This variant was reported in 12/113,726 individuals (MAF 0.005%) in the gnomAD database, which includes ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 10/15,634 Latino individuals (for the highest allele frequency: 0.032%), and 2/51,540 non-Finnish Europeans (MAF 0.002%). 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. Of note, our patient’s ancestry is Latino. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 09, 2022 | 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 - |
Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 08, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 89 of the JUP protein (p.Met89Thr). This variant is present in population databases (rs542745694, gnomAD 0.03%). 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: 583093). 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. - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 05, 2019 | Variant summary: JUP c.266T>C (p.Met89Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 232480 control chromosomes, predominantly at a frequency of 0.00034 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 34 fold of the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.266T>C in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 12, 2021 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;.;T;.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;.;T;T;T;T;T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;.
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;D;D;.
Sift4G
Uncertain
D;D;D;.;.;.;.;D
Polyphen
D;D;D;.;.;.;.;.
Vest4
MutPred
Gain of phosphorylation at M89 (P = 0.0273);Gain of phosphorylation at M89 (P = 0.0273);Gain of phosphorylation at M89 (P = 0.0273);Gain of phosphorylation at M89 (P = 0.0273);Gain of phosphorylation at M89 (P = 0.0273);Gain of phosphorylation at M89 (P = 0.0273);Gain of phosphorylation at M89 (P = 0.0273);Gain of phosphorylation at M89 (P = 0.0273);
MVP
MPC
0.18
ClinPred
T
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