rs558770240

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy 17
Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
cardiomyopathy, dilated, 2E
Inheritance: Unknown, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
hypertrophic cardiomyopathy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
dilated cardiomyopathy
Inheritance: SD Classification: MODERATE Submitted by: ClinGen

JPH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 201798.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 SD,AD,Unknown,AR 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

GnomAD2 exomes

AF:

0.000751

AC:

AN:

102496

AF XY:

0.000610

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 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

African (AFR)

AF:

0.0216

AC:

611

AN:

28230

American (AMR)

AF:

0.000911

AC:

AN:

31816

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23646

East Asian (EAS)

AF:

0.00

AC:

AN:

33188

South Asian (SAS)

AF:

0.0000658

AC:

AN:

75936

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33194

Middle Eastern (MID)

AF:

0.00119

AC:

AN:

4214

European-Non Finnish (NFE)

AF:

0.0000178

AC:

AN:

1064434

Other (OTH)

AF:

0.00157

AC:

AN:

56028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

143

191

239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00587

AC:

890

AN:

151738

Hom.:

Cov.:

AF XY:

0.00609

AC XY:

452

AN XY:

74168

show subpopulations

African (AFR)

AF:

0.0208

AC:

863

AN:

41522

American (AMR)

AF:

0.00125

AC:

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10446

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000590

AC:

AN:

67810

Other (OTH)

AF:

0.00190

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

131

174

218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Apr 12, 2017

Eurofins Ntd Llc (ga)

Significance: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

- -

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

- -

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). -

Hypertrophic cardiomyopathy

Uncertain:1Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Benign:2

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

JPH2: BS1, BS2 -

May 10, 2022

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

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

(source)

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

PhyloP100

6.2

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

Mutation Taster

=75/25

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over