rs761591158

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020433.5(JPH2):c.692G>A(p.Arg231Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000475 in 1,530,048 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 0 hom. )

Consequence

JPH2
NM_020433.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 2.57

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 Submitted by: Labcorp Genetics (formerly Invitae)
dilated cardiomyopathy
Inheritance: SD, AR, AD Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen
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

JPH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20013422).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020433.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH2	NM_020433.5	MANE Select	c.692G>A	p.Arg231Gln	missense	Exon 2 of 6	NP_065166.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
JPH2	ENST00000372980.4	TSL:5 MANE Select	c.692G>A	p.Arg231Gln	missense	Exon 2 of 6	ENSP00000362071.3	Q9BR39-1
JPH2	ENST00000900331.1		c.692G>A	p.Arg231Gln	missense	Exon 2 of 7	ENSP00000570390.1
JPH2	ENST00000950207.1		c.755G>A	p.Arg252Gln	missense	Exon 3 of 7	ENSP00000620266.1

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

151832

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000722

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:

0.000619

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.000241

AC:

AN:

128486

AF XY:

0.000214

show subpopulations

Gnomad AFR exome

AF:

0.000160

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000479

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000486

AC:

670

AN:

1378216

Hom.:

Cov.:

AF XY:

0.000468

AC XY:

318

AN XY:

679460

show subpopulations

African (AFR)

AF:

0.0000958

AC:

AN:

31322

American (AMR)

AF:

0.000198

AC:

AN:

35396

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24960

East Asian (EAS)

AF:

0.00

AC:

AN:

35498

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78950

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34084

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4882

European-Non Finnish (NFE)

AF:

0.000586

AC:

630

AN:

1075640

Other (OTH)

AF:

0.000504

AC:

AN:

57484

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

111

148

185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<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:

0.000375

AC:

AN:

151832

Hom.:

Cov.:

AF XY:

0.000405

AC XY:

AN XY:

74152

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41404

American (AMR)

AF:

0.000722

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000619

AC:

AN:

67882

Other (OTH)

AF:

0.000480

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000323

Hom.:

Bravo

AF:

0.000385

ExAC

AF:

0.0000956

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

Hypertrophic cardiomyopathy (1)

Hypertrophic cardiomyopathy 17 (1)

Hypertrophic cardiomyopathy 17;C5561970:Cardiomyopathy, dilated, 2E (1)

JPH2-related disorder (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Benign

0.045

Eigen_PC

Benign

-0.0057

FATHMM_MKL

Benign

0.19

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.4

PhyloP100

2.6

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.18

Sift

Benign

0.071

Sift4G

Uncertain

0.040

Polyphen

0.97

Vest4

0.16

MVP

0.84

ClinPred

0.43

GERP RS

3.0

Varity_R

0.15

gMVP

0.51

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over