20-44186291-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020433.5(JPH2):c.379+36A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.836 in 1,604,436 control chromosomes in the GnomAD database, including 561,834 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.86 (56211 hom., cov: 27)
  • Exomes 𝑓: 0.83 (505623 hom.)
• Consequence: JPH2 NM_020433.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.491

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 20-44186291-T-C is Benign according to our data. Variant chr20-44186291-T-C is described in ClinVar as [Benign]. Clinvar id is 671113.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-44186291-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JPH2	NM_020433.5	c.379+36A>G		intron_variant		ENST00000372980.4
JPH2	NM_175913.4	c.379+36A>G		intron_variant
JPH2	XM_006723833.5	c.379+36A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JPH2	ENST00000372980.4	c.379+36A>G		intron_variant		5	NM_020433.5	P1
JPH2	ENST00000342272.3	c.379+36A>G		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.860 AC: 130244 AN: 151422 Hom.: 56157 Cov.: 27

Gnomad AFR AF: 0.928

Gnomad AMI AF: 0.726

Gnomad AMR AF: 0.869

Gnomad ASJ AF: 0.824

Gnomad EAS AF: 0.832

Gnomad SAS AF: 0.833

Gnomad FIN AF: 0.836

Gnomad MID AF: 0.818

Gnomad NFE AF: 0.828

Gnomad OTH AF: 0.862

GnomAD3 exomes AF: 0.847 AC: 206046 AN: 243244 Hom.: 87482 AF XY: 0.842 AC XY: 111309 AN XY: 132180

Gnomad AFR exome AF: 0.931

Gnomad AMR exome AF: 0.907

Gnomad ASJ exome AF: 0.832

Gnomad EAS exome AF: 0.828

Gnomad SAS exome AF: 0.843

Gnomad FIN exome AF: 0.839

Gnomad NFE exome AF: 0.824

Gnomad OTH exome AF: 0.837

GnomAD4 exome AF: 0.834 AC: 1211015 AN: 1452896 Hom.: 505623 Cov.: 40 AF XY: 0.833 AC XY: 602277 AN XY: 723012

Gnomad4 AFR exome AF: 0.927

Gnomad4 AMR exome AF: 0.903

Gnomad4 ASJ exome AF: 0.835

Gnomad4 EAS exome AF: 0.877

Gnomad4 SAS exome AF: 0.846

Gnomad4 FIN exome AF: 0.835

Gnomad4 NFE exome AF: 0.825

Gnomad4 OTH exome AF: 0.834

GnomAD4 genome AF: 0.860 AC: 130358 AN: 151540 Hom.: 56211 Cov.: 27 AF XY: 0.860 AC XY: 63694 AN XY: 74030

Gnomad4 AFR AF: 0.928

Gnomad4 AMR AF: 0.869

Gnomad4 ASJ AF: 0.824

Gnomad4 EAS AF: 0.832

Gnomad4 SAS AF: 0.834

Gnomad4 FIN AF: 0.836

Gnomad4 NFE AF: 0.828

Gnomad4 OTH AF: 0.862

Alfa AF: 0.844 Hom.: 9965

Bravo AF: 0.865

Asia WGS AF: 0.829 AC: 2884 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	5.1
Dann	Benign	0.32

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: rs6031442; hg19: chr20-42814931;