chr20-44114814-A-G

Position:

chr20-44114814-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_020433.5(JPH2):c.2073T>C(p.Phe691=) 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:7

Conservation

PhyloP100: 0.322

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr20-44114814-A-G is described in Lovd as [Benign].

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/exons	MANE	UniProt
JPH2	NM_020433.5 linkuse as main transcript	c.2073T>C	p.Phe691=	synonymous_variant	5/6	ENST00000372980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JPH2	ENST00000372980.4 linkuse as main transcript	c.2073T>C	p.Phe691=	synonymous_variant	5/6	5	NM_020433.5	P1	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

GnomAD3 exomes

AF:

0.248

AC:

58346

AN:

235182

Hom.:

8321

AF XY:

0.242

AC XY:

30531

AN XY:

126332

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 SAS exome

AF:

0.120

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

Gnomad4 AFR exome

AF:

0.459

Gnomad4 AMR exome

AF:

0.159

Gnomad4 ASJ exome

AF:

0.324

Gnomad4 EAS exome

AF:

0.0705

Gnomad4 SAS exome

AF:

0.124

Gnomad4 FIN exome

AF:

0.284

Gnomad4 NFE exome

AF:

0.315

Gnomad4 OTH exome

AF:

0.292

GnomAD4 genome

AF:

0.324

AC:

49133

AN:

151676

Hom.:

8569

Cov.:

AF XY:

0.316

AC XY:

23400

AN XY:

74126

show subpopulations

Gnomad4 AFR

AF:

0.458

Gnomad4 AMR

AF:

0.219

Gnomad4 ASJ

AF:

0.325

Gnomad4 EAS

AF:

0.0917

Gnomad4 SAS

AF:

0.117

Gnomad4 FIN

AF:

0.281

Gnomad4 NFE

AF:

0.305

Gnomad4 OTH

AF:

0.311

Alfa

AF:

0.305

Hom.:

9681

Bravo

AF:

0.327

Asia WGS

AF:

0.130

AC:

454

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	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). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Hypertrophic cardiomyopathy 17

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Sep 21, 2015

- -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2015

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

DANN

Benign

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over