rs976272461
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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):āc.620A>Gā(p.Asn207Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,424,314 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 (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.000011 ( 0 hom. )
Consequence
JPH2
NM_020433.5 missense
NM_020433.5 missense
Scores
1
3
15
Clinical Significance
Conservation
PhyloP100: 4.37
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=0.098273724).
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000132 (2/151656) while in subpopulation EAS AF= 0.000388 (2/5154). AF 95% confidence interval is 0.0000686. There are 0 homozygotes in gnomad4. There are 2 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
JPH2 | NM_020433.5 | c.620A>G | p.Asn207Ser | missense_variant | 2/6 | ENST00000372980.4 | NP_065166.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
JPH2 | ENST00000372980.4 | c.620A>G | p.Asn207Ser | missense_variant | 2/6 | 5 | NM_020433.5 | ENSP00000362071.3 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151656Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000439 AC: 2AN: 45520Hom.: 0 AF XY: 0.0000377 AC XY: 1AN XY: 26522
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GnomAD4 exome AF: 0.0000110 AC: 14AN: 1272658Hom.: 0 Cov.: 32 AF XY: 0.00000801 AC XY: 5AN XY: 624394
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 151656Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74082
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
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 | Aug 13, 2021 | - - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 20, 2022 | This variant has not been reported in the literature in individuals affected with JPH2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.04%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 207 of the JPH2 protein (p.Asn207Ser). ClinVar contains an entry for this variant (Variation ID: 454470). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 16, 2021 | The p.N207S variant (also known as c.620A>G), located in coding exon 2 of the JPH2 gene, results from an A to G substitution at nucleotide position 620. The asparagine at codon 207 is replaced by serine, an amino acid with highly similar properties. This amino acid position is conserved. 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
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of glycosylation at N207 (P = 0.0295);
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