20-44159949-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_020433.5(JPH2):c.838G>A(p.Glu280Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000056 in 1,606,576 control chromosomes in the GnomAD database, including 1 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 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 1 hom. )

Consequence

JPH2
NM_020433.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.46

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 -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30313963).

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.838G>A	p.Glu280Lys	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.838G>A	p.Glu280Lys	missense	Exon 2 of 6	ENSP00000362071.3	Q9BR39-1
JPH2	ENST00000900331.1		c.838G>A	p.Glu280Lys	missense	Exon 2 of 7	ENSP00000570390.1
JPH2	ENST00000950207.1		c.901G>A	p.Glu301Lys	missense	Exon 3 of 7	ENSP00000620266.1

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151608

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000625

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000886

AC:

AN:

237046

AF XY:

0.000140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000932

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000591

AC:

AN:

1454856

Hom.:

Cov.:

AF XY:

0.0000816

AC XY:

AN XY:

723296

show subpopulations

African (AFR)

AF:

0.0000899

AC:

AN:

33376

American (AMR)

AF:

0.00

AC:

AN:

44310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25912

East Asian (EAS)

AF:

0.00

AC:

AN:

39568

South Asian (SAS)

AF:

0.000848

AC:

AN:

84940

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50272

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110454

Other (OTH)

AF:

0.000133

AC:

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000264

AC:

AN:

151720

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74150

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41392

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.000625

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10544

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67802

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000824

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypertrophic cardiomyopathy 17 (3)

not provided (2)

Cardiovascular phenotype (1)

Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.4

PhyloP100

7.5

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.29

Sift

Uncertain

0.0060

Sift4G

Benign

0.12

Polyphen

0.94

Vest4

0.39

MutPred

0.47

Gain of sheet (P = 0.0061)

MVP

0.85

ClinPred

0.31

GERP RS

3.0

Varity_R

0.50

gMVP

0.58

Mutation Taster

=64/36

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