rs387906898

Positions:

• chr20-44160293-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_020433.5(JPH2):​c.494C>T​(p.Ser165Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000719 in 1,389,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S165Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: JPH2 NM_020433.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.48

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a compositionally_biased_region Polar residues (size 15) in uniprot entity JPH2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_020433.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-44160293-G-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 20-44160293-G-A is Pathogenic according to our data. Variant chr20-44160293-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30457.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-44160293-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JPH2	NM_020433.5	c.494C>T	p.Ser165Phe	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.494C>T	p.Ser165Phe	missense_variant	2/6	5	NM_020433.5	ENSP00000362071.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000719 AC: 10 AN: 1389970 Hom.: 0 Cov.: 32 AF XY: 0.00000583 AC XY: 4 AN XY: 685686

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000928

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypertrophic cardiomyopathy 17 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.8	M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.76		Loss of phosphorylation at S165 (P = 0.0176);
MVP		0.93
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.87
gMVP		0.70

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: rs387906898; hg19: chr20-42788933;