NM_020433.5:c.2073T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_020433.5(JPH2):c.2073T>C(p.Phe691Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,604,238 control chromosomes in the GnomAD database, including 75,081 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8569 hom., cov: 30)

Exomes 𝑓: 0.29 ( 66512 hom. )

Consequence

JPH2
NM_020433.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.322

Publications

19 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 20-44114814-A-G is Benign according to our data. Variant chr20-44114814-A-G is described in ClinVar as [Benign]. Clinvar id is 137611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.322 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JPH2	NM_020433.5 link	c.2073T>C	p.Phe691Phe	synonymous_variant	Exon 5 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.2073T>C	p.Phe691Phe	synonymous_variant	Exon 5 of 6	5	NM_020433.5	ENSP00000362071.3		Q9BR39-1

Frequencies

GnomAD3 genomes

AF:

0.324

AC:

49063

AN:

151558

Hom.:

8541

Cov.:

show subpopulations

Gnomad AFR

AF:

0.457

Gnomad AMI

AF:

0.411

Gnomad AMR

AF:

0.219

Gnomad ASJ

AF:

0.325

Gnomad EAS

AF:

0.0921

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.281

Gnomad MID

AF:

0.190

Gnomad NFE

AF:

0.305

Gnomad OTH

AF:

0.316

GnomAD2 exomes

AF:

0.248

AC:

58346

AN:

235182

AF XY:

0.242

show subpopulations

Gnomad AFR exome

AF:

0.450

Gnomad AMR exome

AF:

0.150

Gnomad ASJ exome

AF:

0.320

Gnomad EAS exome

AF:

0.0877

Gnomad FIN exome

AF:

0.280

Gnomad NFE exome

AF:

0.297

Gnomad OTH exome

AF:

0.275

GnomAD4 exome

AF:

0.293

AC:

426299

AN:

1452562

Hom.:

66512

Cov.:

AF XY:

0.288

AC XY:

207531

AN XY:

721336

show subpopulations

African (AFR)

AF:

0.459

AC:

15342

AN:

33414

American (AMR)

AF:

0.159

AC:

6919

AN:

43456

Ashkenazi Jewish (ASJ)

AF:

0.324

AC:

8369

AN:

25814

East Asian (EAS)

AF:

0.0705

AC:

2783

AN:

39480

South Asian (SAS)

AF:

0.124

AC:

10381

AN:

83998

European-Finnish (FIN)

AF:

0.284

AC:

14981

AN:

52708

Middle Eastern (MID)

AF:

0.222

AC:

1272

AN:

5742

European-Non Finnish (NFE)

AF:

0.315

AC:

348681

AN:

1107848

Other (OTH)

AF:

0.292

AC:

17571

AN:

60102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

15318

30636

45953

61271

76589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.324

AC:

49133

AN:

151676

Hom.:

8569

Cov.:

AF XY:

0.316

AC XY:

23400

AN XY:

74126

show subpopulations

African (AFR)

AF:

0.458

AC:

18919

AN:

41308

American (AMR)

AF:

0.219

AC:

3337

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.325

AC:

1127

AN:

3466

East Asian (EAS)

AF:

0.0917

AC:

472

AN:

5148

South Asian (SAS)

AF:

0.117

AC:

560

AN:

4784

European-Finnish (FIN)

AF:

0.281

AC:

2954

AN:

10528

Middle Eastern (MID)

AF:

0.190

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.305

AC:

20682

AN:

67876

Other (OTH)

AF:

0.311

AC:

655

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1625

3250

4875

6500

8125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.306

Hom.:

11281

Bravo

AF:

0.327

Asia WGS

AF:

0.130

AC:

454

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 08, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Phe691Phe in exon 5 of JPH2: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 44.8% (1973/4404) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs6093935). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hypertrophic cardiomyopathy 17

Benign:1

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 15, 2015

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

BayesDel_noAF

Benign

-0.66

CADD

Benign

5.9

(source)

DANN

Benign

0.68

PhyloP100

0.32

Mutation Taster

=100/0

polymorphism (auto)

(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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NM_020433.5:c.2073T>C

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