rs376612687

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_020433.5(JPH2):c.1852A>G(p.Thr618Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000283 in 1,601,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T618N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

JPH2
NM_020433.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0400

Publications

0 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.032173336).

BP6

Variant 20-44115823-T-C is Benign according to our data. Variant chr20-44115823-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 432626.

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.1852A>G	p.Thr618Ala	missense	Exon 4 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.1852A>G	p.Thr618Ala	missense	Exon 4 of 6	ENSP00000362071.3	Q9BR39-1
JPH2	ENST00000900331.1		c.1933A>G	p.Thr645Ala	missense	Exon 5 of 7	ENSP00000570390.1
JPH2	ENST00000950207.1		c.1915A>G	p.Thr639Ala	missense	Exon 5 of 7	ENSP00000620266.1

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

151840

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000383

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000204

AC:

AN:

230472

AF XY:

0.000260

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000877

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000703

Gnomad NFE exome

AF:

0.000414

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000295

AC:

427

AN:

1449574

Hom.:

Cov.:

AF XY:

0.000297

AC XY:

214

AN XY:

721198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33396

American (AMR)

AF:

0.0000897

AC:

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39624

South Asian (SAS)

AF:

0.00

AC:

AN:

86122

European-Finnish (FIN)

AF:

0.0000228

AC:

AN:

43932

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5624

European-Non Finnish (NFE)

AF:

0.000374

AC:

415

AN:

1110088

Other (OTH)

AF:

0.000116

AC:

AN:

60118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000178

AC:

AN:

151840

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74154

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41336

American (AMR)

AF:

0.0000655

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000383

AC:

AN:

67958

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.000506

Hom.:

Bravo

AF:

0.000204

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000216

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (3)

Cardiovascular phenotype (1)

Hypertrophic cardiomyopathy (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.48

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.068

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0059

LIST_S2

Benign

0.31

M_CAP

Benign

0.046

MetaRNN

Benign

0.032

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.1

PhyloP100

-0.040

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.47

REVEL

Benign

0.17

Sift

Benign

0.20

Sift4G

Benign

0.79

Polyphen

0.0

Vest4

0.039

MVP

0.52

ClinPred

0.063

GERP RS

-6.4

Varity_R

0.024

gMVP

0.18

Mutation Taster

=94/6

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