rs574746149

Positions:

chr20-44160225-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020433.5(JPH2):c.562C>T(p.Pro188Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000371 in 1,483,740 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 3 hom. )

Consequence

JPH2
NM_020433.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.84

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 (MetaRNN=0.0029876828).

BP6

Variant 20-44160225-G-A is Benign according to our data. Variant chr20-44160225-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 220441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44160225-G-A is described in Lovd as [Benign]. Variant chr20-44160225-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00201 (305/152062) while in subpopulation AFR AF= 0.00688 (286/41548). AF 95% confidence interval is 0.00623. There are 1 homozygotes in gnomad4. There are 148 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JPH2	NM_020433.5 linkuse as main transcript	c.562C>T	p.Pro188Ser	missense_variant	2/6	ENST00000372980.4	NP_065166.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JPH2	ENST00000372980.4 linkuse as main transcript	c.562C>T	p.Pro188Ser	missense_variant	2/6	5	NM_020433.5	ENSP00000362071	P1	Q9BR39-1

Frequencies

GnomAD3 genomes

AF:

0.00199

AC:

302

AN:

151954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00683

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000984

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000418

AC:

AN:

90832

Hom.:

AF XY:

0.000297

AC XY:

AN XY:

50536

show subpopulations

Gnomad AFR exome

AF:

0.0126

Gnomad AMR exome

AF:

0.000650

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000659

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000282

Gnomad OTH exome

AF:

0.000347

GnomAD4 exome

AF:

0.000184

AC:

245

AN:

1331678

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

106

AN XY:

653742

show subpopulations

Gnomad4 AFR exome

AF:

0.00658

Gnomad4 AMR exome

AF:

0.00100

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000853

Gnomad4 OTH exome

AF:

0.000451

GnomAD4 genome

AF:

0.00201

AC:

305

AN:

152062

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00688

Gnomad4 AMR

AF:

0.000983

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.00225

ExAC

AF:

0.0000941

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 04, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

JPH2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jan 22, 2019

- -

Hypertrophic cardiomyopathy 17

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 31, 2017

- -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2018

This alteration is classified as likely 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

0.064

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.041

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.49

MetaRNN

Benign

0.0030

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.14

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.070

REVEL

Benign

0.035

Sift

Benign

1.0

Sift4G

Benign

0.79

Polyphen

0.15

Vest4

0.15

MVP

0.71

ClinPred

0.0082

GERP RS

2.3

Varity_R

0.049

gMVP

0.23

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