20-44118607-C-T

Position:

chr20-44118607-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020433.5(JPH2):c.1186G>A(p.Ala396Thr) variant causes a missense change. The variant allele was found at a frequency of 0.151 in 1,610,126 control chromosomes in the GnomAD database, including 23,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3808 hom., cov: 33)

Exomes 𝑓: 0.15 ( 19449 hom. )

Consequence

JPH2
NM_020433.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 4.34

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=0.001573354).

BP6

Variant 20-44118607-C-T is Benign according to our data. Variant chr20-44118607-C-T is described in ClinVar as [Benign]. Clinvar id is 137607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44118607-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 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.1186G>A	p.Ala396Thr	missense_variant	3/6	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.1186G>A	p.Ala396Thr	missense_variant	3/6	5	NM_020433.5	ENSP00000362071.3		Q9BR39-1

Frequencies

GnomAD3 genomes

AF:

0.201

AC:

30543

AN:

152098

Hom.:

3802

Cov.:

show subpopulations

Gnomad AFR

AF:

0.337

Gnomad AMI

AF:

0.0888

Gnomad AMR

AF:

0.143

Gnomad ASJ

AF:

0.143

Gnomad EAS

AF:

0.365

Gnomad SAS

AF:

0.280

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.132

Gnomad OTH

AF:

0.192

GnomAD3 exomes

AF:

0.178

AC:

44187

AN:

248698

Hom.:

5099

AF XY:

0.183

AC XY:

24600

AN XY:

134678

show subpopulations

Gnomad AFR exome

AF:

0.348

Gnomad AMR exome

AF:

0.0969

Gnomad ASJ exome

AF:

0.158

Gnomad EAS exome

AF:

0.363

Gnomad SAS exome

AF:

0.285

Gnomad FIN exome

AF:

0.104

Gnomad NFE exome

AF:

0.134

Gnomad OTH exome

AF:

0.157

GnomAD4 exome

AF:

0.146

AC:

212865

AN:

1457908

Hom.:

19449

Cov.:

AF XY:

0.150

AC XY:

109141

AN XY:

725510

show subpopulations

Gnomad4 AFR exome

AF:

0.349

Gnomad4 AMR exome

AF:

0.102

Gnomad4 ASJ exome

AF:

0.153

Gnomad4 EAS exome

AF:

0.411

Gnomad4 SAS exome

AF:

0.282

Gnomad4 FIN exome

AF:

0.102

Gnomad4 NFE exome

AF:

0.123

Gnomad4 OTH exome

AF:

0.156

GnomAD4 genome

AF:

0.201

AC:

30565

AN:

152218

Hom.:

3808

Cov.:

AF XY:

0.200

AC XY:

14912

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.336

Gnomad4 AMR

AF:

0.143

Gnomad4 ASJ

AF:

0.143

Gnomad4 EAS

AF:

0.365

Gnomad4 SAS

AF:

0.280

Gnomad4 FIN

AF:

0.107

Gnomad4 NFE

AF:

0.132

Gnomad4 OTH

AF:

0.198

Alfa

AF:

0.153

Hom.:

4016

Bravo

AF:

0.208

TwinsUK

AF:

0.118

AC:

436

ALSPAC

AF:

0.122

AC:

469

ESP6500AA

AF:

0.330

AC:

1455

ESP6500EA

AF:

0.129

AC:

1109

ExAC

AF:

0.184

AC:

22344

Asia WGS

AF:

0.311

AC:

1082

AN:

3478

EpiCase

AF:

0.142

EpiControl

AF:

0.146

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 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	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ala396Thr in exon 3 of JPH2: This variant is not expected to have clinical signi ficance because it has been identified in 33.0% (1455/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs3810510). -

Hypertrophic cardiomyopathy 17

Benign:2

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jun 06, 2016

- -

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

Jun 15, 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

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.17

Sift

Benign

0.12

Sift4G

Benign

0.14

Polyphen

0.97

Vest4

0.17

ClinPred

0.027

GERP RS

3.8

Varity_R

0.17

gMVP

0.75

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