chr20-44160305-G-C

Position:

• chr20-44160305-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020433.5(JPH2):​c.482C>G​(p.Thr161Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T161T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: JPH2 NM_020433.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.20

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JPH2	NM_020433.5	c.482C>G	p.Thr161Arg	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.482C>G	p.Thr161Arg	missense_variant	2/6	5	NM_020433.5	ENSP00000362071.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.28		Gain of MoRF binding (P = 0.0369);
MVP		0.94
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.85
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: rs587782951; hg19: chr20-42788945;