rs6093935

chr20-44114814-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.322

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]

ACMG classification

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	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	c.2073T>C	p.Phe691=	synonymous_variant	5/6	5	NM_020433.5	P1

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49063 AN: 151558 Hom.: 8541 Cov.: 30

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

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.: 35 AF XY: 0.288 AC XY: 207531 AN XY: 721336

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.: 30 AF XY: 0.316 AC XY: 23400 AN XY: 74126

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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. -

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

Invitae

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

Other links and lift over

dbSNP: rs6093935; hg19: chr20-42743454; COSMIC: COSV65902426;