rs1326977511
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_020433.5(JPH2):c.1306C>T(p.Arg436Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000444 in 1,395,570 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000044 ( 1 hom. )
Failed GnomAD Quality Control
Consequence
JPH2
NM_020433.5 missense
NM_020433.5 missense
Scores
2
11
6
Clinical Significance
Conservation
PhyloP100: 4.30
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000444 (62/1395570) while in subpopulation EAS AF= 0.00174 (62/35704). AF 95% confidence interval is 0.00139. There are 1 homozygotes in gnomad4_exome. There are 31 alleles in male gnomad4_exome subpopulation. Median coverage is 34. 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 | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| JPH2 | NM_020433.5 | c.1306C>T | p.Arg436Cys | missense_variant | 4/6 | ENST00000372980.4 | NP_065166.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| JPH2 | ENST00000372980.4 | c.1306C>T | p.Arg436Cys | missense_variant | 4/6 | 5 | NM_020433.5 | ENSP00000362071 | P1 |
Frequencies
GnomAD3 genomes 0.00 AC: 2AN: 152166Hom.: 0 Cov.: 32 FAILED QC
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GnomAD3 exomes AF: 0.0000360 AC: 5AN: 139018Hom.: 0 AF XY: 0.0000265 AC XY: 2AN XY: 75454
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GnomAD4 exome AF: 0.0000444 AC: 62AN: 1395570Hom.: 1 Cov.: 34 AF XY: 0.0000450 AC XY: 31AN XY: 688332
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GnomAD4 genome 0.0000131 AC: 2AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74344
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Data not reliable, filtered out with message: AS_VQSR
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
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 | Feb 02, 2018 | Variant p.Arg436Cys in JPH2 c.1306C>T in exon 4 NM_020433.4, hg19, chr20-42745009-G-A SCICD classification Variant of uncertain significance We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: limited case data and some evidence it may be a polymorphism in Japanese populations. Gene-level evidence JPH2: JPH2 encodes junctophilin-2, which forms a junctional complex between the plasma membrane and endoplasmic/sarcoplasmic reticulum. It may play a role in calcium signaling in cardiomyocytes. Takeshima et al. (2000) showed that Jp2 is abundantly expressed in mouse heart, and mutant mice lacking Jp2 exhibited embryonic lethality. Cardiac myocytes from the mutant mice showed deficiency of the junctional membrane complexes and abnormal calcium transients. Population-level data per the ExAC database indicates that JPH2 is relatively tolerant to loss of function variation (pLI=0.01) in humans, but constrained in regards to missense variation (z=3.94). JPH2 is considered a gene of uncertain significance as few studies linking JPH2 to hypertrophic cardiomyopathy have been published. Case data summary Reported in 2 unrelated cases of HCM. No segregation data available. Not listed in ClinVar. Please see below for a detailed review of case data. Predicted Consequence Per the test report, "there is a large physicochemical difference between arginine and cysteine." Experimental Data None available for review In silico data Per the test 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: "Possibly Damaging"; Align-GVGD: "Class C0")." Conservation Per the test report, "The arginine residue is moderately conserved" Nearby pathogenic variation There is no pathogenic variation at this codon or nearby codons listed in ClinVar. Population Data Highest MAF in East Asian population in gnomAD: 0.06173% Matsushita et al., 2007: 2/236 Japanese patients (MAF=0.847%) Note that this site has poor coverage in gnomAD. Please see below for details. Case data for p.Arg436Cys (does not include this patient): 2 cases of HCM, no segregation data. · ClinVar: not present · Cases in the literature: · Matsushita et al., 2007: Mutation of junctophilin type 2 associated with hypertrophic cardiomyopathy: 2 out of 148 Japanese patients with HCM and 2 out of 236 Japanese controls. The authors suggest that this variant may be a polymorphism. Population data for p.Arg436Cys: Highest MAF in East Asian population: 0.06173%. The variant was reported online in 1 of 15,451 total individuals (MAF: 0.06173%) in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, and Latino descent. Specifically, the variant was observed in: 1 of 810 individuals of East Asian descent (MAF=0.06173%) Per Matsushita et al., 2007: 2/236 Japanese patients (MAF=0.847%). The phenotype of those individuals is not publicly available. The dataset is composed of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). As of February 2, 2018 the average coverage at that site in gnomAD for exomes is: Mean coverage 27x, Median coverage 19x, and 249% of samples over 20x coverage. The average coverage at that site in gnomAD for genomes is unavailable for review. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 17, 2019 | Identified in two unrelated patients with HCM and two healthy controls in the published literature (Matsushita et al., 2007); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar by another clinical laboratory as a variant of uncertain clinical significance (ClinVar Variant ID# 454468; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 17476457, 22515980, 24636942) - |
Hypertrophic cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 19, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 436 of the JPH2 protein (p.Arg436Cys). 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 missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 17476457). ClinVar contains an entry for this variant (Variation ID: 454468). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 | Mar 13, 2018 | The p.R436C variant (also known as c.1306C>T), located in coding exon 4 of the JPH2 gene, results from a C to T substitution at nucleotide position 1306. The arginine at codon 436 is replaced by cysteine, an amino acid with highly dissimilar properties. In one Japanese study, this alteration was detected in two individuals with hypertrophic cardiomyopathy and in two healthy controls; however, clinical details were limited (Matsushita Y et al. J. Hum. Genet., 2007 May;52:543-8). This amino acid position is 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
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of solvent accessibility (P = 0.0036);
MVP
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