rs147407445

chr20-44118589-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BS1_Supporting

The NM_020433.5(JPH2):c.1204G>A(p.Glu402Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 1,612,178 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (1 hom.)
• Consequence: JPH2 NM_020433.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:4
• Conservation: PhyloP100: 7.31

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3264467).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000355 (54/152254) while in subpopulation NFE AF= 0.000691 (47/68044). AF 95% confidence interval is 0.000533. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. 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.1204G>A	p.Glu402Lys	missense_variant	3/6	ENST00000372980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JPH2	ENST00000372980.4	c.1204G>A	p.Glu402Lys	missense_variant	3/6	5	NM_020433.5	P1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000284 AC: 71 AN: 249762 Hom.: 1 AF XY: 0.000326 AC XY: 44 AN XY: 135174

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000498

Gnomad NFE exome AF: 0.000563

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000760 AC: 1110 AN: 1459924 Hom.: 1 Cov.: 32 AF XY: 0.000721 AC XY: 524 AN XY: 726414

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000583

Gnomad4 NFE exome AF: 0.000974

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74396

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000971 Hom.: 1

Bravo AF: 0.000408

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.000600

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 07, 2017	The p.Glu402Lys variant (rs147407445) has been reported in ClinVar, but not in the medical literature. This variant is listed in the Genome Aggregation Database (gnomAD) Browser with an overall population frequency of 0.03 percent (identified on 81 out of 275,606 chromosomes). The glutamic acid at position 402 is highly conserved from human to sea squirt (Alamut v2.9.0), and computational analyses of the effects of the p.Glu402Lys variant on protein structure and function is conflicting (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Glu402Lys variant with certainty. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2016	A variant of uncertain significance has been identified in the JPH2 gene. The E402K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, it has previously been identified in other unrelated individuals who underwent genetic testing for cardiomyopathy or sudden unexpected death at GeneDx and has been classified as a variant of uncertain significance by another clinical laboratory (Landrum et al., 2014). The E402K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where only amino acids with similar properties to Glutamic acid are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The NHLBI Exome Sequencing Project reports E402K was observed in 8/8,600 alleles from individuals of European background. Furthermore, only one missense variant in a nearby residue (A405S) has been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 15, 2023	Variant summary: JPH2 c.1204G>A (p.Glu402Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 249762 control chromosomes (gnomAD), predominantly at a frequency of 0.00056 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 22 fold of the estimated maximal expected allele frequency for a pathogenic variant in JPH2 causing Cardiomyopathy (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters have assessed the variant since 2014: all have classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 01, 2015	The p.Glu402Lys variant in JPH2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 38/66478 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs147407445). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Glu402Lys variant is uncertain. -

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Nov 14, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 402 of the JPH2 protein (p.Glu402Lys). This variant is present in population databases (rs147407445, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with JPH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 188245). 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. -

Hypertrophic cardiomyopathy 17;C5561970:Cardiomyopathy, dilated, 2E Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 02, 2021

- -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

-

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The p.E402K variant (also known as c.1204G>A), located in coding exon 3 of the JPH2 gene, results from a G to A substitution at nucleotide position 1204. The glutamic acid at codon 402 is replaced by lysine, an amino acid with similar properties. This variant was observed in a stillbirth case which was tested on a next-generation sequencing panel for cardiac cardiomyopathy and channelopathy genes; however, clinical details were limited (Sahlin E et al. PLoS One, 2019 Jan;14:e0210017). 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	Benign	0.27
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.25
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.19
Sift	Benign	0.040	D
Sift4G	Benign	0.20	T
Polyphen		0.98	D
Vest4		0.54
MVP		0.83
ClinPred		0.35	T
GERP RS		4.8
Varity_R		0.26
gMVP		0.87

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

Other links and lift over

dbSNP: rs147407445; hg19: chr20-42747229;