20-44116162-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020433.5(JPH2):c.1513G>A(p.Gly505Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00623 in 1,414,254 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G505R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.010 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 57 hom. )

Consequence

JPH2
NM_020433.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:16

Conservation

PhyloP100: 0.0110

Publications

29 publications found

Variant links:

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

JPH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019930005).

BP6

Variant 20-44116162-C-T is Benign according to our data. Variant chr20-44116162-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 30458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0102 (1556/152064) while in subpopulation SAS AF = 0.0242 (117/4828). AF 95% confidence interval is 0.0207. There are 10 homozygotes in GnomAd4. There are 778 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 SD,AD,Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JPH2	NM_020433.5 link	c.1513G>A	p.Gly505Ser	missense_variant	Exon 4 of 6	ENST00000372980.4	NP_065166.2	Q9BR39-1Q86VZ3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JPH2	ENST00000372980.4 link	c.1513G>A	p.Gly505Ser	missense_variant	Exon 4 of 6	5	NM_020433.5	ENSP00000362071.3		Q9BR39-1

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1557

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0188

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.00214

Gnomad SAS

AF:

0.0246

Gnomad FIN

AF:

0.00850

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.00559

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00913

AC:

236

AN:

25840

AF XY:

0.00963

show subpopulations

Gnomad AFR exome

AF:

0.0202

Gnomad AMR exome

AF:

0.00364

Gnomad ASJ exome

AF:

0.0253

Gnomad EAS exome

AF:

0.00175

Gnomad FIN exome

AF:

0.0150

Gnomad NFE exome

AF:

0.00534

Gnomad OTH exome

AF:

0.00488

GnomAD4 exome

AF:

0.00575

AC:

7258

AN:

1262190

Hom.:

Cov.:

AF XY:

0.00613

AC XY:

3775

AN XY:

615738

show subpopulations

African (AFR)

AF:

0.0190

AC:

469

AN:

24694

American (AMR)

AF:

0.00349

AC:

AN:

16346

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

343

AN:

18088

East Asian (EAS)

AF:

0.00483

AC:

145

AN:

30036

South Asian (SAS)

AF:

0.0211

AC:

1269

AN:

60002

European-Finnish (FIN)

AF:

0.0112

AC:

341

AN:

30530

Middle Eastern (MID)

AF:

0.0165

AC:

AN:

3692

European-Non Finnish (NFE)

AF:

0.00404

AC:

4143

AN:

1026618

Other (OTH)

AF:

0.00824

AC:

430

AN:

52184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

440

879

1319

1758

2198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

320

480

640

800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0102

AC:

1556

AN:

152064

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

778

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0187

AC:

777

AN:

41504

American (AMR)

AF:

0.00490

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

AN:

3470

East Asian (EAS)

AF:

0.00215

AC:

AN:

5118

South Asian (SAS)

AF:

0.0242

AC:

117

AN:

4828

European-Finnish (FIN)

AF:

0.00850

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00559

AC:

380

AN:

67934

Other (OTH)

AF:

0.00851

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

156

234

312

390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00466

Hom.:

Bravo

AF:

0.00952

ESP6500AA

AF:

0.0146

AC:

ESP6500EA

AF:

0.00400

AC:

ExAC

AF:

0.00564

AC:

382

Asia WGS

AF:

0.0190

AC:

AN:

3460

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jun 10, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 28, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Gly505Ser in exon 4 of JPH2: This variant is not expected to have clinical sig nificance because it has been identified in 7.3% (30/412) of South Asian chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; rs140740776). -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 19, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy 17

Uncertain:1Benign:4

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 08, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 01, 2007

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 01, 2017

Phosphorus, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

JPH2: BS1, BS2 -

Oct 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 20, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25333069, 27532831, 23299917, 17476457, 27884173, 29398688) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hypertrophic cardiomyopathy

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 14, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

9.3

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.056

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

0.011

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.13

REVEL

Benign

0.084

Sift

Benign

0.62

Sift4G

Benign

0.71

Polyphen

0.019

Vest4

0.12

MVP

0.59

ClinPred

0.00041

GERP RS

1.0

Varity_R

0.046

gMVP

0.30

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over