rs748233107
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_020433.5(JPH2):c.1033G>C(p.Val345Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,613,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_020433.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JPH2 | NM_020433.5 | c.1033G>C | p.Val345Leu | missense_variant | 2/6 | ENST00000372980.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JPH2 | ENST00000372980.4 | c.1033G>C | p.Val345Leu | missense_variant | 2/6 | 5 | NM_020433.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152238Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000598 AC: 15AN: 250792Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135678
GnomAD4 exome AF: 0.000107 AC: 157AN: 1461380Hom.: 0 Cov.: 33 AF XY: 0.0000922 AC XY: 67AN XY: 727050
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74372
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 17;C5561970:Cardiomyopathy, dilated, 2E Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 09, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2021 | Identified patient with drug-induced Long QT syndrome whose baseline QTc was 399 milliseconds (Ramirez et al., 2013); however, no additional clinical or segregation data were provided; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 454466; Landrum et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23834499, 22584458) - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 24, 2023 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 454466). This missense change has been observed in individual(s) with drug-induced arrhythmia (PMID: 22584458). This variant is present in population databases (rs748233107, gnomAD 0.009%). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 345 of the JPH2 protein (p.Val345Leu). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 16, 2023 | The p.V345L variant (also known as c.1033G>C), located in coding exon 2 of the JPH2 gene, results from a G to C substitution at nucleotide position 1033. The valine at codon 345 is replaced by leucine, an amino acid with highly similar properties. This variant has been detected in an individual from a drug-induced arrhythmia cohort (Ramirez AH et al. Pharmacogenomics J, 2013 Aug;13:325-9). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at