20-44115885-G-A

Variant names:

• chr20-44115885-G-A
• rs775179837
• NM_020433.5:c.1790C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020433.5(JPH2):​c.1790C>T​(p.Ser597Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000042 in 1,428,648 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. S597W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000042 (1 hom.)
• Consequence: JPH2 NM_020433.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.33
• 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, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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
• dilated cardiomyopathy

  Inheritance: SD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12023625).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH2	NM_020433.5	MANE Select	c.1790C>T	p.Ser597Leu	missense	Exon 4 of 6	NP_065166.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH2	ENST00000372980.4	TSL:5 MANE Select	c.1790C>T	p.Ser597Leu	missense	Exon 4 of 6	ENSP00000362071.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000420 AC: 6 AN: 1428648 Hom.: 1 Cov.: 33 AF XY: 0.00000564 AC XY: 4 AN XY: 709222

African (AFR) AF: 0.0000303 AC: 1 AN: 32994

American (AMR) AF: 0.00 AC: 0 AN: 42218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25626

East Asian (EAS) AF: 0.00 AC: 0 AN: 39010

South Asian (SAS) AF: 0.00 AC: 0 AN: 84642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37674

Middle Eastern (MID) AF: 0.000367 AC: 2 AN: 5444

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1101782

Other (OTH) AF: 0.00 AC: 0 AN: 59258

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:1

Feb 11, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with JPH2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with leucine at codon 597 of the JPH2 protein (p.Ser597Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.072
Sift	Benign	0.23	T
Sift4G	Benign	0.32	T
Polyphen		0.012	B
Vest4		0.17
MutPred		0.16		Loss of phosphorylation at S597 (P = 0.0057)
MVP		0.74
ClinPred		0.20	T
GERP RS		2.0
Varity_R		0.040
gMVP		0.23
Mutation Taster		=88/12	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: rs775179837; hg19: chr20-42744525;