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):ā€‹c.58G>Cā€‹(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 (ā˜…). 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: š‘“ 0.0000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.000011 ( 0 hom. )

Consequence

JPH2
NM_020433.5 missense

Scores

1
6
12

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]

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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 UniProt
JPH2NM_020433.5 linkuse as main transcriptc.58G>C p.Gly20Arg missense_variant 1/6 ENST00000372980.4
JPH2NM_175913.4 linkuse as main transcriptc.58G>C p.Gly20Arg missense_variant 1/2
JPH2XM_006723833.5 linkuse as main transcriptc.58G>C p.Gly20Arg missense_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
JPH2ENST00000372980.4 linkuse as main transcriptc.58G>C p.Gly20Arg missense_variant 1/65 NM_020433.5 P1Q9BR39-1
JPH2ENST00000342272.3 linkuse as main transcriptc.58G>C p.Gly20Arg missense_variant 1/21 Q9BR39-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152164
Hom.:
0
Cov.:
33
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:
4
AN:
243174
Hom.:
0
AF XY:
0.0000151
AC XY:
2
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:
16
AN:
1456292
Hom.:
0
Cov.:
38
AF XY:
0.0000110
AC XY:
8
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:
1
AN:
152164
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
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:
1
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 submitterclinical testingAmbry GeneticsJul 22, 2021The 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
T
BayesDel_noAF
Benign
-0.39
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.19
T;.
Eigen
Benign
-0.079
Eigen_PC
Benign
0.025
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Benign
0.073
D
MetaRNN
Benign
0.20
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.69
N;N
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.69
T
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
D
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.

Other links and lift over

dbSNP: rs988100071; hg19: chr20-42815288; API