20-44115971-G-C

Variant names:

• chr20-44115971-G-C
• rs200892606
• NM_020433.5:c.1704C>G

Variant summary

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

The NM_020433.5(JPH2):​c.1704C>G​(p.Ser568Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. S568S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: JPH2 NM_020433.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.20
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1704C>G	p.Ser568Arg	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.1704C>G	p.Ser568Arg	missense	Exon 4 of 6	ENSP00000362071.3	Q9BR39-1
	JPH2	ENST00000900331.1		c.1785C>G	p.Ser595Arg	missense	Exon 5 of 7	ENSP00000570390.1
	JPH2	ENST00000950207.1		c.1767C>G	p.Ser589Arg	missense	Exon 5 of 7	ENSP00000620266.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424454 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 707056

African (AFR) AF: 0.0000304 AC: 1 AN: 32948

American (AMR) AF: 0.00 AC: 0 AN: 41304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25638

East Asian (EAS) AF: 0.00 AC: 0 AN: 38696

South Asian (SAS) AF: 0.00 AC: 0 AN: 83740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100886

Other (OTH) AF: 0.00 AC: 0 AN: 59378

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.19
Sift	Uncertain	0.015	D
Sift4G	Benign	0.19	T
Polyphen		0.10	B
Vest4		0.35
MutPred		0.26		Gain of MoRF binding (P = 0.0305)
MVP		0.82
ClinPred		0.29	T
GERP RS		2.4
Varity_R		0.18
gMVP		0.67
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200892606; hg19: chr20-42744611;