Genetic Variant JPH2:c.379+36A>G (chr20-44186291-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.491

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 -20 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_multiple_submitters_no_conflicts, 2 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	Effect	Exon rank	MANE	Protein	UniProt
JPH2	NM_020433.5 link	c.379+36A>G	intron_variant	Intron 1 of 5	ENST00000372980.4	NP_065166.2	Q9BR39-1Q86VZ3
JPH2	NM_175913.4 link	c.379+36A>G	intron_variant	Intron 1 of 1		NP_787109.2	Q9BR39-2
JPH2	XM_006723833.5 link	c.379+36A>G	intron_variant	Intron 1 of 1		XP_006723896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JPH2	ENST00000372980.4 link	c.379+36A>G		intron_variant	Intron 1 of 5	5	NM_020433.5	ENSP00000362071.3		Q9BR39-1
JPH2	ENST00000342272.3 link	c.379+36A>G		intron_variant	Intron 1 of 1	1		ENSP00000344590.3		Q9BR39-2

Frequencies

GnomAD3 genomes

AF:

0.860

AC:

130244

AN:

151422

Hom.:

56157

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.833

AC XY:

602277

AN XY:

723012

show subpopulations

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.:

AF XY:

0.860

AC XY:

63694

AN XY:

74030

show subpopulations

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:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

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. -

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

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