rs908217758

Variant names:

• chr20-44116072-G-A
• rs908217758
• NM_020433.5:c.1603C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-44116072-G-A
• chr20-44116072-G-T
• chr20-44116072-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020433.5(JPH2):​c.1603C>T​(p.Pro535Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. P535T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: JPH2 NM_020433.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71
• Publications: 0 publications found

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]

JPH2 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy 17

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: SD, AR, AD Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen
• cardiomyopathy, dilated, 2E

  Inheritance: Unknown, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15358815).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020433.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH2	NM_020433.5	MANE Select	c.1603C>T	p.Pro535Ser	missense	Exon 4 of 6	NP_065166.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH2	ENST00000372980.4	TSL:5 MANE Select	c.1603C>T	p.Pro535Ser	missense	Exon 4 of 6	ENSP00000362071.3	Q9BR39-1
	JPH2	ENST00000900331.1		c.1684C>T	p.Pro562Ser	missense	Exon 5 of 7	ENSP00000570390.1
	JPH2	ENST00000950207.1		c.1666C>T	p.Pro556Ser	missense	Exon 5 of 7	ENSP00000620266.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383538 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 684926

African (AFR) AF: 0.00 AC: 0 AN: 29344

American (AMR) AF: 0.00 AC: 0 AN: 35466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23912

East Asian (EAS) AF: 0.00 AC: 0 AN: 35508

South Asian (SAS) AF: 0.00 AC: 0 AN: 78052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4820

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1084158

Other (OTH) AF: 0.00 AC: 0 AN: 57542

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.060	N
REVEL	Benign	0.046
Sift	Benign	0.13	T
Sift4G	Benign	0.66	T
Polyphen		0.075	B
Vest4		0.22
MutPred		0.22		Gain of phosphorylation at P535 (P = 7e-04)
MVP		0.69
ClinPred		0.12	T
GERP RS		1.9
Varity_R		0.056
gMVP		0.42
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs908217758; hg19: chr20-42744712;