rs757257639

chr20-44159918-G-Achr20-44159918-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_020433.5(JPH2):c.869C>T(p.Thr290Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000308 in 1,459,682 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T290S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000031 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: JPH2 NM_020433.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.02

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_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27450183).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JPH2	NM_020433.5	c.869C>T	p.Thr290Ile	missense_variant	2/6	ENST00000372980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JPH2	ENST00000372980.4	c.869C>T	p.Thr290Ile	missense_variant	2/6	5	NM_020433.5	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 150 AN: 130300 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00134

Gnomad AMR AF: 0.00126

Gnomad ASJ AF: 0.000674

Gnomad EAS AF: 0.00140

Gnomad SAS AF: 0.000720

Gnomad FIN AF: 0.000411

Gnomad MID AF: 0.00901

Gnomad NFE AF: 0.00108

Gnomad OTH AF: 0.00112

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245792 Hom.: 0 AF XY: 0.00000751 AC XY: 1 AN XY: 133118

Gnomad AFR exome AF: 0.0000631

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 0.0000308 AC: 45 AN: 1459682 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 726050

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: 0.0000405

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00115 AC: 150 AN: 130416 Hom.: 0 Cov.: 31 AF XY: 0.00112 AC XY: 72 AN XY: 64142

Gnomad4 AFR AF: 0.00145

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.000674

Gnomad4 EAS AF: 0.00141

Gnomad4 SAS AF: 0.000720

Gnomad4 FIN AF: 0.000411

Gnomad4 NFE AF: 0.00108

Gnomad4 OTH AF: 0.00111

Alfa AF: 0.000868 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 05, 2021

- -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 17, 2023

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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 241295). This variant has not been reported in the literature in individuals affected with JPH2-related conditions. 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 sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 290 of the JPH2 protein (p.Thr290Ile). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 2023

The p.T290I variant (also known as c.869C>T), located in coding exon 2 of the JPH2 gene, results from a C to T substitution at nucleotide position 869. The threonine at codon 290 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not 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	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.96	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.057
Sift	Benign	0.047	D
Sift4G	Benign	0.29	T
Polyphen		0.059	B
Vest4		0.42
MutPred		0.35		Gain of catalytic residue at T290 (P = 0.0188);
MVP		0.66
ClinPred		0.18	T
GERP RS		2.0
Varity_R		0.20
gMVP		0.40

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: rs757257639; hg19: chr20-42788558;