rs558770240

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020433.5(JPH2):c.661T>C(p.Phe221Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0011 in 1,502,424 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0059 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 6 hom. )

Consequence

JPH2
NM_020433.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: 6.24

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008279234).

BP6

Variant 20-44160126-A-G is Benign according to our data. Variant chr20-44160126-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201798.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=6, Uncertain_significance=1}. Variant chr20-44160126-A-G is described in Lovd as [Benign]. Variant chr20-44160126-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00587 (890/151738) while in subpopulation AFR AF= 0.0208 (863/41522). AF 95% confidence interval is 0.0196. There are 10 homozygotes in gnomad4. There are 452 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 rank	MANE	Protein	UniProt
JPH2	NM_020433.5 link	c.661T>C	p.Phe221Leu	missense_variant	Exon 2 of 6	ENST00000372980.4	NP_065166.2	Q9BR39-1Q86VZ3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JPH2	ENST00000372980.4 link	c.661T>C	p.Phe221Leu	missense_variant	Exon 2 of 6	5	NM_020433.5	ENSP00000362071.3		Q9BR39-1

Frequencies

GnomAD3 genomes

AF:

0.00588

AC:

891

AN:

151630

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0208

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000590

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000751

AC:

AN:

102496

Hom.:

AF XY:

0.000610

AC XY:

AN XY:

57350

show subpopulations

Gnomad AFR exome

AF:

0.0208

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000506

Gnomad OTH exome

AF:

0.000625

GnomAD4 exome

AF:

0.000560

AC:

757

AN:

1350686

Hom.:

Cov.:

AF XY:

0.000461

AC XY:

307

AN XY:

665360

show subpopulations

Gnomad4 AFR exome

AF:

0.0216

Gnomad4 AMR exome

AF:

0.000911

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000658

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000178

Gnomad4 OTH exome

AF:

0.00157

GnomAD4 genome

AF:

0.00587

AC:

890

AN:

151738

Hom.:

Cov.:

AF XY:

0.00609

AC XY:

452

AN XY:

74168

show subpopulations

Gnomad4 AFR

AF:

0.0208

Gnomad4 AMR

AF:

0.00125

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000590

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00309

Hom.:

ExAC

AF:

0.000781

AC:

Asia WGS

AF:

0.000585

AC:

AN:

3432

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Oct 22, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Phe221Leu in exon 2 of JPH2: This variant is not expected to have clinical sig nificance due to high population frequency. It has been identified in 4.82% (8/ 166) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org; rs558770240). -

Apr 12, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 19, 2019

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy

Uncertain:1Benign:1

Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

May 10, 2022

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

JPH2: BS1, BS2 -

Hypertrophic cardiomyopathy 17

Uncertain:1

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

JPH2-related disorder

Benign:1

Sep 13, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Cardiovascular phenotype

Benign:1

Mar 06, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Pathogenic

0.81

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

Eigen

Benign

0.14

Eigen_PC

Benign

0.044

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0083

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.5

PrimateAI

Pathogenic

0.95

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.25

Sift

Benign

0.17

Sift4G

Benign

0.17

Polyphen

0.99

Vest4

0.50

MutPred

0.39

Gain of helix (P = 0.0696);

MVP

0.76

ClinPred

0.082

GERP RS

2.0

Varity_R

0.33

gMVP

0.74

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