20-44116162-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020433.5(JPH2):c.1513G>A(p.Gly505Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00623 in 1,414,254 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G505R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.010 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 57 hom. )

Consequence

JPH2
NM_020433.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:16

Conservation

PhyloP100: 0.0110

Publications

29 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019930005).

BP6

Variant 20-44116162-C-T is Benign according to our data. Variant chr20-44116162-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 30458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0102 (1556/152064) while in subpopulation SAS AF = 0.0242 (117/4828). AF 95% confidence interval is 0.0207. There are 10 homozygotes in GnomAd4. There are 778 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

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

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.1513G>A	p.Gly505Ser	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.1513G>A	p.Gly505Ser	missense	Exon 4 of 6	ENSP00000362071.3	Q9BR39-1
JPH2	ENST00000900331.1		c.1594G>A	p.Gly532Ser	missense	Exon 5 of 7	ENSP00000570390.1
JPH2	ENST00000950207.1		c.1576G>A	p.Gly526Ser	missense	Exon 5 of 7	ENSP00000620266.1

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1557

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0188

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.00214

Gnomad SAS

AF:

0.0246

Gnomad FIN

AF:

0.00850

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.00559

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00913

AC:

236

AN:

25840

AF XY:

0.00963

show subpopulations

Gnomad AFR exome

AF:

0.0202

Gnomad AMR exome

AF:

0.00364

Gnomad ASJ exome

AF:

0.0253

Gnomad EAS exome

AF:

0.00175

Gnomad FIN exome

AF:

0.0150

Gnomad NFE exome

AF:

0.00534

Gnomad OTH exome

AF:

0.00488

GnomAD4 exome

AF:

0.00575

AC:

7258

AN:

1262190

Hom.:

Cov.:

AF XY:

0.00613

AC XY:

3775

AN XY:

615738

show subpopulations

African (AFR)

AF:

0.0190

AC:

469

AN:

24694

American (AMR)

AF:

0.00349

AC:

AN:

16346

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

343

AN:

18088

East Asian (EAS)

AF:

0.00483

AC:

145

AN:

30036

South Asian (SAS)

AF:

0.0211

AC:

1269

AN:

60002

European-Finnish (FIN)

AF:

0.0112

AC:

341

AN:

30530

Middle Eastern (MID)

AF:

0.0165

AC:

AN:

3692

European-Non Finnish (NFE)

AF:

0.00404

AC:

4143

AN:

1026618

Other (OTH)

AF:

0.00824

AC:

430

AN:

52184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

440

879

1319

1758

2198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

320

480

640

800

<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:

0.0102

AC:

1556

AN:

152064

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

778

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0187

AC:

777

AN:

41504

American (AMR)

AF:

0.00490

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

AN:

3470

East Asian (EAS)

AF:

0.00215

AC:

AN:

5118

South Asian (SAS)

AF:

0.0242

AC:

117

AN:

4828

European-Finnish (FIN)

AF:

0.00850

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00559

AC:

380

AN:

67934

Other (OTH)

AF:

0.00851

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

156

234

312

390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00466

Hom.:

Bravo

AF:

0.00952

ESP6500AA

AF:

0.0146

AC:

ESP6500EA

AF:

0.00400

AC:

ExAC

AF:

0.00564

AC:

382

Asia WGS

AF:

0.0190

AC:

AN:

3460

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Hypertrophic cardiomyopathy 17 (5)

not provided (4)

Cardiovascular phenotype (1)

Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

9.3

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.056

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

0.011

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.13

REVEL

Benign

0.084

Sift

Benign

0.62

Sift4G

Benign

0.71

Polyphen

0.019

Vest4

0.12

MVP

0.59

ClinPred

0.00041

GERP RS

1.0

Varity_R

0.046

gMVP

0.30

Mutation Taster

=96/4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over