20-44186648-C-G

Position:

chr20-44186648-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_020433.5(JPH2):c.58G>C(p.Gly20Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000106 in 1,608,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G20W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

JPH2
NM_020433.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.73

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20476523).

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000011 (16/1456292) while in subpopulation SAS AF= 0.000139 (12/86254). AF 95% confidence interval is 0.00008. There are 0 homozygotes in gnomad4_exome. There are 8 alleles in male gnomad4_exome subpopulation. Median coverage is 38. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
JPH2	NM_020433.5 linkuse as main transcript	c.58G>C	p.Gly20Arg	missense_variant	1/6	ENST00000372980.4
JPH2	NM_175913.4 linkuse as main transcript	c.58G>C	p.Gly20Arg	missense_variant	1/2
JPH2	XM_006723833.5 linkuse as main transcript	c.58G>C	p.Gly20Arg	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JPH2	ENST00000372980.4 linkuse as main transcript	c.58G>C	p.Gly20Arg	missense_variant	1/6	5	NM_020433.5	P1	Q9BR39-1
JPH2	ENST00000342272.3 linkuse as main transcript	c.58G>C	p.Gly20Arg	missense_variant	1/2	1			Q9BR39-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

243174

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

132248

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000983

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000904

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1456292

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

724736

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 22, 2021

The p.G20R variant (also known as c.58G>C), located in coding exon 1 of the JPH2 gene, results from a G to C substitution at nucleotide position 58. The glycine at codon 20 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-0.079

Eigen_PC

Benign

0.025

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.073

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.9

N;D

REVEL

Benign

0.13

Sift

Uncertain

0.011

D;D

Sift4G

Uncertain

0.035

D;T

Polyphen

1.0

D;B

Vest4

0.30

MutPred

0.34

Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);

MVP

0.77

ClinPred

0.78

GERP RS

3.6

Varity_R

0.23

gMVP

0.39

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