rs74352869

Positions:

chr20-44115947-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_020433.5(JPH2):c.1728C>G(p.Pro576Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,567,210 control chromosomes in the GnomAD database, including 38,820 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 3786 hom., cov: 32)

Exomes 𝑓: 0.22 ( 35034 hom. )

Consequence

JPH2
NM_020433.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.416

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 20-44115947-G-C is Benign according to our data. Variant chr20-44115947-G-C is described in ClinVar as [Benign]. Clinvar id is 137609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44115947-G-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.416 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JPH2	NM_020433.5 linkuse as main transcript	c.1728C>G	p.Pro576Pro	synonymous_variant	4/6	ENST00000372980.4	NP_065166.2	Q9BR39-1Q86VZ3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JPH2	ENST00000372980.4 linkuse as main transcript	c.1728C>G	p.Pro576Pro	synonymous_variant	4/6	5	NM_020433.5	ENSP00000362071.3		Q9BR39-1

Frequencies

GnomAD3 genomes

AF:

0.217

AC:

32982

AN:

151938

Hom.:

3774

Cov.:

show subpopulations

Gnomad AFR

AF:

0.256

Gnomad AMI

AF:

0.324

Gnomad AMR

AF:

0.151

Gnomad ASJ

AF:

0.235

Gnomad EAS

AF:

0.0679

Gnomad SAS

AF:

0.0827

Gnomad FIN

AF:

0.216

Gnomad MID

AF:

0.137

Gnomad NFE

AF:

0.228

Gnomad OTH

AF:

0.199

GnomAD3 exomes

AF:

0.170

AC:

29150

AN:

171214

Hom.:

2879

AF XY:

0.168

AC XY:

16020

AN XY:

95344

show subpopulations

Gnomad AFR exome

AF:

0.254

Gnomad AMR exome

AF:

0.108

Gnomad ASJ exome

AF:

0.229

Gnomad EAS exome

AF:

0.0644

Gnomad SAS exome

AF:

0.0839

Gnomad FIN exome

AF:

0.219

Gnomad NFE exome

AF:

0.223

Gnomad OTH exome

AF:

0.190

GnomAD4 exome

AF:

0.215

AC:

304879

AN:

1415164

Hom.:

35034

Cov.:

AF XY:

0.211

AC XY:

148255

AN XY:

701612

show subpopulations

Gnomad4 AFR exome

AF:

0.255

Gnomad4 AMR exome

AF:

0.112

Gnomad4 ASJ exome

AF:

0.233

Gnomad4 EAS exome

AF:

0.0477

Gnomad4 SAS exome

AF:

0.0839

Gnomad4 FIN exome

AF:

0.221

Gnomad4 NFE exome

AF:

0.234

Gnomad4 OTH exome

AF:

0.205

GnomAD4 genome

AF:

0.217

AC:

33025

AN:

152046

Hom.:

3786

Cov.:

AF XY:

0.212

AC XY:

15785

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.256

Gnomad4 AMR

AF:

0.150

Gnomad4 ASJ

AF:

0.235

Gnomad4 EAS

AF:

0.0677

Gnomad4 SAS

AF:

0.0828

Gnomad4 FIN

AF:

0.216

Gnomad4 NFE

AF:

0.228

Gnomad4 OTH

AF:

0.197

Alfa

AF:

0.221

Hom.:

712

Bravo

AF:

0.215

Asia WGS

AF:

0.0860

AC:

298

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Pro576Pro in exon 4 of JPH2: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 18.9% (1430/7580) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs74352869). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2013	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. -

Hypertrophic cardiomyopathy 17

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 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

-0.88

CADD

Benign

0.96

DANN

Benign

0.55

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