NM_020433.5:c.156C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020433.5(JPH2):c.156C>T(p.Tyr52Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.836 in 1,613,862 control chromosomes in the GnomAD database, including 565,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.86 ( 56829 hom., cov: 31)

Exomes 𝑓: 0.83 ( 508580 hom. )

Consequence

JPH2
NM_020433.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 2.27

Publications

22 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 (BayesDel_noAF=-0.61).

BP6

Variant 20-44186550-G-A is Benign according to our data. Variant chr20-44186550-G-A is described in ClinVar as Benign. ClinVar VariationId is 137602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JPH2	NM_020433.5 link	c.156C>T	p.Tyr52Tyr	synonymous_variant	Exon 1 of 6	ENST00000372980.4	NP_065166.2	Q9BR39-1Q86VZ3
JPH2	NM_175913.4 link	c.156C>T	p.Tyr52Tyr	synonymous_variant	Exon 1 of 2		NP_787109.2	Q9BR39-2
JPH2	XM_006723833.5 link	c.156C>T	p.Tyr52Tyr	synonymous_variant	Exon 1 of 2		XP_006723896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JPH2	ENST00000372980.4 link	c.156C>T	p.Tyr52Tyr	synonymous_variant	Exon 1 of 6	5	NM_020433.5	ENSP00000362071.3		Q9BR39-1
JPH2	ENST00000342272.3 link	c.156C>T	p.Tyr52Tyr	synonymous_variant	Exon 1 of 2	1		ENSP00000344590.3		Q9BR39-2

Frequencies

GnomAD3 genomes

AF:

0.863

AC:

131113

AN:

151972

Hom.:

56769

Cov.:

show subpopulations

Gnomad AFR

AF:

0.936

Gnomad AMI

AF:

0.726

Gnomad AMR

AF:

0.877

Gnomad ASJ

AF:

0.835

Gnomad EAS

AF:

0.751

Gnomad SAS

AF:

0.830

Gnomad FIN

AF:

0.839

Gnomad MID

AF:

0.813

Gnomad NFE

AF:

0.833

Gnomad OTH

AF:

0.864

GnomAD2 exomes

AF:

0.846

AC:

212362

AN:

251152

AF XY:

0.840

show subpopulations

Gnomad AFR exome

AF:

0.939

Gnomad AMR exome

AF:

0.915

Gnomad ASJ exome

AF:

0.845

Gnomad EAS exome

AF:

0.748

Gnomad FIN exome

AF:

0.847

Gnomad NFE exome

AF:

0.829

Gnomad OTH exome

AF:

0.838

GnomAD4 exome

AF:

0.833

AC:

1218304

AN:

1461772

Hom.:

508580

Cov.:

AF XY:

0.833

AC XY:

605477

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.936

AC:

31336

AN:

33478

American (AMR)

AF:

0.911

AC:

40751

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.847

AC:

22133

AN:

26134

East Asian (EAS)

AF:

0.743

AC:

29502

AN:

39698

South Asian (SAS)

AF:

0.839

AC:

72377

AN:

86258

European-Finnish (FIN)

AF:

0.843

AC:

44976

AN:

53360

Middle Eastern (MID)

AF:

0.835

AC:

4814

AN:

5768

European-Non Finnish (NFE)

AF:

0.829

AC:

921950

AN:

1111962

Other (OTH)

AF:

0.836

AC:

50465

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

13588

27175

40763

54350

67938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21026

42052

63078

84104

105130

<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:

0.863

AC:

131234

AN:

152090

Hom.:

56829

Cov.:

AF XY:

0.863

AC XY:

64140

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.936

AC:

38849

AN:

41518

American (AMR)

AF:

0.877

AC:

13412

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.835

AC:

2898

AN:

3470

East Asian (EAS)

AF:

0.751

AC:

3845

AN:

5120

South Asian (SAS)

AF:

0.831

AC:

4012

AN:

4826

European-Finnish (FIN)

AF:

0.839

AC:

8894

AN:

10596

Middle Eastern (MID)

AF:

0.810

AC:

238

AN:

294

European-Non Finnish (NFE)

AF:

0.833

AC:

56602

AN:

67958

Other (OTH)

AF:

0.864

AC:

1822

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

919

1839

2758

3678

4597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

892

1784

2676

3568

4460

<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:

0.844

Hom.:

85894

Bravo

AF:

0.867

Asia WGS

AF:

0.815

AC:

2834

AN:

3478

EpiCase

AF:

0.832

EpiControl

AF:

0.822

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Jan 08, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Tyr52Tyr in exon 1 of JPH2: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 17.1% (1468/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs1883790). -

Jun 20, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Hypertrophic cardiomyopathy 17

Benign:3

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

- -

Aug 19, 2021

Genome-Nilou Lab

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

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy, dilated, 2E

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 11, 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

BayesDel_noAF

Benign

-0.61

CADD

Benign

6.6

(source)

DANN

Benign

0.52

PhyloP100

2.3

Mutation Taster

=100/0

polymorphism (auto)

(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

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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