rs74352869

chr20-44115947-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020433.5(JPH2):c.1728C>G(p.Pro576=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.416

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]

ACMG classification

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	UniProt
JPH2	NM_020433.5	c.1728C>G	p.Pro576=	synonymous_variant	4/6	ENST00000372980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JPH2	ENST00000372980.4	c.1728C>G	p.Pro576=	synonymous_variant	4/6	5	NM_020433.5	P1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32982 AN: 151938 Hom.: 3774 Cov.: 32

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

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.: 37 AF XY: 0.211 AC XY: 148255 AN XY: 701612

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.: 32 AF XY: 0.212 AC XY: 15785 AN XY: 74324

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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. -
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	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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 19, 2015	- -

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	- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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

Other links and lift over

dbSNP: rs74352869; hg19: chr20-42744587; COSMIC: COSV65902448;