rs761591158
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_020433.5(JPH2):c.692G>A(p.Arg231Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000475 in 1,530,048 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00049 ( 0 hom. )
Consequence
JPH2
NM_020433.5 missense
NM_020433.5 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: 2.57
Genes affected
JPH2 (HGNC:14202): (junctophilin 2) Junctional complexes between the plasma membrane and endoplasmic/sarcoplasmic reticulum are a common feature of all excitable cell types and mediate cross talk between cell surface and intracellular ion channels. The protein encoded by this gene is a component of junctional complexes and is composed of a C-terminal hydrophobic segment spanning the endoplasmic/sarcoplasmic reticulum membrane and a remaining cytoplasmic domain that shows specific affinity for the plasma membrane. This gene is a member of the junctophilin gene family. Alternative splicing has been observed at this locus and two variants encoding distinct isoforms are described. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.20013422).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000375 (57/151832) while in subpopulation AMR AF= 0.000722 (11/15240). AF 95% confidence interval is 0.00047. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JPH2 | NM_020433.5 | c.692G>A | p.Arg231Gln | missense_variant | 2/6 | ENST00000372980.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JPH2 | ENST00000372980.4 | c.692G>A | p.Arg231Gln | missense_variant | 2/6 | 5 | NM_020433.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000375 AC: 57AN: 151832Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000241 AC: 31AN: 128486Hom.: 0 AF XY: 0.000214 AC XY: 15AN XY: 70138
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GnomAD4 exome AF: 0.000486 AC: 670AN: 1378216Hom.: 0 Cov.: 32 AF XY: 0.000468 AC XY: 318AN XY: 679460
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GnomAD4 genome AF: 0.000375 AC: 57AN: 151832Hom.: 0 Cov.: 32 AF XY: 0.000405 AC XY: 30AN XY: 74152
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy 17;C5561970:Cardiomyopathy, dilated, 2E Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 21, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 14, 2023 | Reported in an individual with DCM, who also harbored a missense variant in the HCN4 gene, and in an individual with RCM (Arbustini et al., 2017; van Lint et al., 2019); Also reported in an abstract as a de novo occurrence in a proband undergoing whole exome sequencing (Tang et al., 2013); however, a pathogenic splice site variant in the MYBPC3 gene was also identified, which was inherited from an affected parent; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28254189, 30235249, 25356970, 30847666, 35001666, 28771489) - |
Hypertrophic cardiomyopathy 17 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 17 (MIM# 613873). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (57 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as either likely benign or a VUS in the literature and by multiple clinical diagnostic laboratories, and has been identified in individuals with either dilated cardiomyopathy, hypertrophic cardiomyopathy or restrictive cardiomyopathy (ClinVar; PMIDs: 28771489, 28254189, 30847666). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 231 of the JPH2 protein (p.Arg231Gln). This variant is present in population databases (rs761591158, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with JPH2-related conditions (PMID: 28254189, 28771489, 30847666). ClinVar contains an entry for this variant (Variation ID: 225099). 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 disruptive. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 26, 2023 | The p.R231Q variant (also known as c.692G>A), located in coding exon 2 of the JPH2 gene, results from a G to A substitution at nucleotide position 692. The arginine at codon 231 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in cardiomyopathy genetic testing cohorts; however, clinical details were limited (Mademont-Soler I et al. PLoS One, 2017 Aug;12:e0181465; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
N
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
N
REVEL
Benign
Sift
Benign
T
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
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