chr20-44116369-G-A

Position:

chr20-44116369-G-A

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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 4.30

Variant links:

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]

JPH2 links:

Genome browser will be placed here

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 linkuse as main transcript	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 linkuse as main transcript	c.1306C>T	p.Arg436Cys	missense_variant	4/6	5	NM_020433.5	ENSP00000362071	P1	Q9BR39-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152166

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000360

AC:

AN:

139018

Hom.:

AF XY:

0.0000265

AC XY:

AN XY:

75454

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000472

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000444

AC:

AN:

1395570

Hom.:

Cov.:

AF XY:

0.0000450

AC XY:

AN XY:

688332

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00174

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000131

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

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. Â· ClinVar: not present Â· Cases in the literature: Â· 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.70

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.22

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.022

Polyphen

1.0

Vest4

0.67

MutPred

0.38

Loss of solvent accessibility (P = 0.0036);

MVP

0.88

ClinPred

0.60

GERP RS

3.3

Varity_R

0.21

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over