chr20-44159931-T-C

Position:

chr20-44159931-T-C

Variant summary

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

The NM_020433.5(JPH2):c.856A>G(p.Thr286Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,560,836 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00097 ( 4 hom. )

Consequence

JPH2
NM_020433.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.58

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=0.0151696205).

BP6

Variant 20-44159931-T-C is Benign according to our data. Variant chr20-44159931-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 201799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44159931-T-C is described in Lovd as [Benign]. Variant chr20-44159931-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00171 (175/102542) while in subpopulation NFE AF= 0.00231 (108/46852). AF 95% confidence interval is 0.00195. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JPH2	NM_020433.5 linkuse as main transcript	c.856A>G	p.Thr286Ala	missense_variant	2/6	ENST00000372980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JPH2	ENST00000372980.4 linkuse as main transcript	c.856A>G	p.Thr286Ala	missense_variant	2/6	5	NM_020433.5	P1	Q9BR39-1

Frequencies

GnomAD3 genomes

AF:

0.00171

AC:

175

AN:

102428

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000273

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000190

Gnomad ASJ

AF:

0.000830

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00671

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00230

Gnomad OTH

AF:

0.000787

GnomAD3 exomes

AF:

0.000997

AC:

243

AN:

243780

Hom.:

AF XY:

0.00105

AC XY:

139

AN XY:

131970

show subpopulations

Gnomad AFR exome

AF:

0.000192

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.000404

Gnomad EAS exome

AF:

0.0000549

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00358

Gnomad NFE exome

AF:

0.00138

Gnomad OTH exome

AF:

0.000828

GnomAD4 exome

AF:

0.000970

AC:

1414

AN:

1458294

Hom.:

Cov.:

AF XY:

0.000924

AC XY:

670

AN XY:

725220

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000180

Gnomad4 ASJ exome

AF:

0.000192

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00375

Gnomad4 NFE exome

AF:

0.00103

Gnomad4 OTH exome

AF:

0.000995

GnomAD4 genome

AF:

0.00171

AC:

175

AN:

102542

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

AN XY:

50496

show subpopulations

Gnomad4 AFR

AF:

0.000272

Gnomad4 AMR

AF:

0.000190

Gnomad4 ASJ

AF:

0.000830

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00671

Gnomad4 NFE

AF:

0.00231

Gnomad4 OTH

AF:

0.000779

Alfa

AF:

0.000737

Hom.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00110

AC:

133

EpiCase

AF:

0.000981

EpiControl

AF:

0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 18, 2015	p.Thr286Ala in exon 2 of JPH2: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (27/5220) of Finnish chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs144022614). -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 06, 2022	- -

Supraventricular tachycardia;C0878544:Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Apr 01, 2019

- -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 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

0.30

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.15

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-3.7

REVEL

Benign

0.25

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.019

Polyphen

0.92

Vest4

0.56

MVP

0.87

ClinPred

0.16

GERP RS

3.0

Varity_R

0.60

gMVP

0.47

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