chr20-44116393-G-A

Position:

• chr20-44116393-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020433.5(JPH2):​c.1289-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,546,950 control chromosomes in the GnomAD database, including 631 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (42 hom., cov: 32)
  • Exomes 𝑓: 0.026 (589 hom.)
• Consequence: JPH2 NM_020433.5 splice_region, intron
• Scores: Splicing: ADA: 0.00007215
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0320

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-44116393-G-A is Benign according to our data. Variant chr20-44116393-G-A is described in ClinVar as [Benign]. Clinvar id is 137608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44116393-G-A is described in Lovd as [Benign]. Variant chr20-44116393-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0205 (3120/152314) while in subpopulation NFE AF= 0.0306 (2083/68012). AF 95% confidence interval is 0.0295. There are 42 homozygotes in gnomad4. There are 1523 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 42 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JPH2	NM_020433.5	c.1289-7C>T		splice_region_variant, intron_variant		ENST00000372980.4	NP_065166.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JPH2	ENST00000372980.4	c.1289-7C>T		splice_region_variant, intron_variant		5	NM_020433.5	ENSP00000362071.3

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3119 AN: 152198 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.00524

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.0311

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0306

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.0189 AC: 2616 AN: 138096 Hom.: 40 AF XY: 0.0190 AC XY: 1428 AN XY: 75004

Gnomad AFR exome AF: 0.00430

Gnomad AMR exome AF: 0.0155

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00632

Gnomad FIN exome AF: 0.0260

Gnomad NFE exome AF: 0.0306

Gnomad OTH exome AF: 0.0207

GnomAD4 exome AF: 0.0265 AC: 36894 AN: 1394636 Hom.: 589 Cov.: 34 AF XY: 0.0261 AC XY: 17943 AN XY: 687918

Gnomad4 AFR exome AF: 0.00403

Gnomad4 AMR exome AF: 0.0157

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00636

Gnomad4 FIN exome AF: 0.0265

Gnomad4 NFE exome AF: 0.0304

Gnomad4 OTH exome AF: 0.0205

GnomAD4 genome AF: 0.0205 AC: 3120 AN: 152314 Hom.: 42 Cov.: 32 AF XY: 0.0204 AC XY: 1523 AN XY: 74486

Gnomad4 AFR AF: 0.00522

Gnomad4 AMR AF: 0.0226

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00683

Gnomad4 FIN AF: 0.0311

Gnomad4 NFE AF: 0.0306

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0257 Hom.: 22

Bravo AF: 0.0191

Asia WGS AF: 0.00491 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	1289-7C>T in intron 3 of JPH2: This variant is not expected to have clinical sig nificance because it has been identified in 3.8% (7/186) of Finnish chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov /projects/SNP; dbSNP rs116986535). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Hypertrophic cardiomyopathy 17 Benign:2

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 04, 2016	- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.6
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000072
dbscSNV1_RF	Benign	0.0
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: rs116986535; hg19: chr20-42745033;