rs1883790

Positions:

chr20-44186550-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 137602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44186550-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
JPH2	NM_020433.5 link	c.156C>T	p.Tyr52Tyr	synonymous_variant	1/6	ENST00000372980.4	NP_065166.2	Q9BR39-1Q86VZ3
JPH2	NM_175913.4 link	c.156C>T	p.Tyr52Tyr	synonymous_variant	1/2		NP_787109.2	Q9BR39-2
JPH2	XM_006723833.5 link	c.156C>T	p.Tyr52Tyr	synonymous_variant	1/2		XP_006723896.1

Ensembl

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

GnomAD3 exomes

AF:

0.846

AC:

212362

AN:

251152

Hom.:

90007

AF XY:

0.840

AC XY:

114017

AN XY:

135762

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 SAS exome

AF:

0.836

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

Gnomad4 AFR exome

AF:

0.936

Gnomad4 AMR exome

AF:

0.911

Gnomad4 ASJ exome

AF:

0.847

Gnomad4 EAS exome

AF:

0.743

Gnomad4 SAS exome

AF:

0.839

Gnomad4 FIN exome

AF:

0.843

Gnomad4 NFE exome

AF:

0.829

Gnomad4 OTH exome

AF:

0.836

GnomAD4 genome

AF:

0.863

AC:

131234

AN:

152090

Hom.:

56829

Cov.:

AF XY:

0.863

AC XY:

64140

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.936

Gnomad4 AMR

AF:

0.877

Gnomad4 ASJ

AF:

0.835

Gnomad4 EAS

AF:

0.751

Gnomad4 SAS

AF:

0.831

Gnomad4 FIN

AF:

0.839

Gnomad4 NFE

AF:

0.833

Gnomad4 OTH

AF:

0.864

Alfa

AF:

0.840

Hom.:

68396

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 20, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	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). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hypertrophic cardiomyopathy 17

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiomyopathy, dilated, 2E

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2015

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

DANN

Benign

0.52

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over