NM_020433.5:c.98A>G

Variant names:

• chr20-44186608-T-C
• rs573848816
• NM_020433.5:c.98A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020433.5(JPH2):​c.98A>G​(p.Lys33Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: JPH2 NM_020433.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.59

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29496366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JPH2	NM_020433.5	c.98A>G	p.Lys33Arg	missense_variant	Exon 1 of 6	ENST00000372980.4	NP_065166.2
JPH2	NM_175913.4	c.98A>G	p.Lys33Arg	missense_variant	Exon 1 of 2		NP_787109.2
JPH2	XM_006723833.5	c.98A>G	p.Lys33Arg	missense_variant	Exon 1 of 2		XP_006723896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JPH2	ENST00000372980.4	c.98A>G	p.Lys33Arg	missense_variant	Exon 1 of 6	5	NM_020433.5	ENSP00000362071.3
JPH2	ENST00000342272.3	c.98A>G	p.Lys33Arg	missense_variant	Exon 1 of 2	1		ENSP00000344590.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249580 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135098

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 39

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74468

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:1

Mar 05, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces lysine with arginine at codon 33 of the JPH2 protein (p.Lys33Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs573848816, ExAC 0.006%). This variant has not been reported in the literature in individuals with JPH2-related disease. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.3	N;D
REVEL	Benign	0.22
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.037	D;T
Polyphen		1.0	D;P
Vest4		0.57
MutPred		0.29		Loss of ubiquitination at K33 (P = 0.0116);Loss of ubiquitination at K33 (P = 0.0116);
MVP		0.88
ClinPred		0.95	D
GERP RS		4.6
Varity_R		0.45
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs573848816; hg19: chr20-42815248;