20-44116162-C-T

Position:

chr20-44116162-C-T

Variant summary

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

The NM_020433.5(JPH2):c.1513G>A(p.Gly505Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00623 in 1,414,254 control chromosomes in the GnomAD database, including 67 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 0.010 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 57 hom. )

Consequence

JPH2
NM_020433.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:15

Conservation

PhyloP100: 0.0110

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=0.0019930005).

BP6

Variant 20-44116162-C-T is Benign according to our data. Variant chr20-44116162-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 30458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44116162-C-T is described in Lovd as [Benign]. Variant chr20-44116162-C-T is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0102 (1556/152064) while in subpopulation SAS AF= 0.0242 (117/4828). AF 95% confidence interval is 0.0207. There are 10 homozygotes in gnomad4. There are 778 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JPH2	NM_020433.5 linkuse as main transcript	c.1513G>A	p.Gly505Ser	missense_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.1513G>A	p.Gly505Ser	missense_variant	4/6	5	NM_020433.5	ENSP00000362071.3		Q9BR39-1

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1557

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0188

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.00214

Gnomad SAS

AF:

0.0246

Gnomad FIN

AF:

0.00850

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.00559

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00913

AC:

236

AN:

25840

Hom.:

AF XY:

0.00963

AC XY:

138

AN XY:

14336

show subpopulations

Gnomad AFR exome

AF:

0.0202

Gnomad AMR exome

AF:

0.00364

Gnomad ASJ exome

AF:

0.0253

Gnomad EAS exome

AF:

0.00175

Gnomad SAS exome

AF:

0.0292

Gnomad FIN exome

AF:

0.0150

Gnomad NFE exome

AF:

0.00534

Gnomad OTH exome

AF:

0.00488

GnomAD4 exome

AF:

0.00575

AC:

7258

AN:

1262190

Hom.:

Cov.:

AF XY:

0.00613

AC XY:

3775

AN XY:

615738

show subpopulations

Gnomad4 AFR exome

AF:

0.0190

Gnomad4 AMR exome

AF:

0.00349

Gnomad4 ASJ exome

AF:

0.0190

Gnomad4 EAS exome

AF:

0.00483

Gnomad4 SAS exome

AF:

0.0211

Gnomad4 FIN exome

AF:

0.0112

Gnomad4 NFE exome

AF:

0.00404

Gnomad4 OTH exome

AF:

0.00824

GnomAD4 genome

AF:

0.0102

AC:

1556

AN:

152064

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

778

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0187

Gnomad4 AMR

AF:

0.00490

Gnomad4 ASJ

AF:

0.0199

Gnomad4 EAS

AF:

0.00215

Gnomad4 SAS

AF:

0.0242

Gnomad4 FIN

AF:

0.00850

Gnomad4 NFE

AF:

0.00559

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00466

Hom.:

Bravo

AF:

0.00952

ESP6500AA

AF:

0.0146

AC:

ESP6500EA

AF:

0.00400

AC:

ExAC

AF:

0.00564

AC:

382

Asia WGS

AF:

0.0190

AC:

AN:

3460

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 17

Uncertain:1Benign:4

Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Sep 08, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 28, 2015	p.Gly505Ser in exon 4 of JPH2: This variant is not expected to have clinical sig nificance because it has been identified in 7.3% (30/412) of South Asian chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; rs140740776). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -
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+	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	JPH2: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2018	This variant is associated with the following publications: (PMID: 25333069, 27532831, 23299917, 17476457, 27884173, 29398688) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 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

0.079

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

9.3

DANN

Benign

0.80

DEOGEN2

Benign

0.056

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.13

REVEL

Benign

0.084

Sift

Benign

0.62

Sift4G

Benign

0.71

Polyphen

0.019

Vest4

0.12

MVP

0.59

ClinPred

0.00041

GERP RS

1.0

Varity_R

0.046

gMVP

0.30

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