rs556886570

Variant summary

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

The NM_020433.5(JPH2):​c.1357C>T​(p.Pro453Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,544,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

JPH2
NM_020433.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.39
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]

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=0.08481997).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000118 (18/152258) while in subpopulation AFR AF= 0.000385 (16/41568). AF 95% confidence interval is 0.000241. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. 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 Protein UniProt
JPH2NM_020433.5 linkuse as main transcriptc.1357C>T p.Pro453Ser missense_variant 4/6 ENST00000372980.4 NP_065166.2 Q9BR39-1Q86VZ3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
JPH2ENST00000372980.4 linkuse as main transcriptc.1357C>T p.Pro453Ser missense_variant 4/65 NM_020433.5 ENSP00000362071.3 Q9BR39-1

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152140
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000386
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000369
AC:
5
AN:
135600
Hom.:
0
AF XY:
0.0000271
AC XY:
2
AN XY:
73808
show subpopulations
Gnomad AFR exome
AF:
0.000170
Gnomad AMR exome
AF:
0.000167
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000129
AC:
18
AN:
1391848
Hom.:
0
Cov.:
34
AF XY:
0.0000131
AC XY:
9
AN XY:
686572
show subpopulations
Gnomad4 AFR exome
AF:
0.000224
Gnomad4 AMR exome
AF:
0.000141
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.28e-7
Gnomad4 OTH exome
AF:
0.0000693
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152258
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.000385
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000113
Hom.:
0
Bravo
AF:
0.000102

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 17;C5561970:Cardiomyopathy, dilated, 2E Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 20, 2021- -
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2024This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 453 of the JPH2 protein (p.Pro453Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with JPH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 264361). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 28, 2022The p.P453S variant (also known as c.1357C>T), located in coding exon 4 of the JPH2 gene, results from a C to T substitution at nucleotide position 1357. The proline at codon 453 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. 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
Benign
0.069
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.11
T
Eigen
Benign
-0.56
Eigen_PC
Benign
-0.51
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.44
T
M_CAP
Benign
0.042
D
MetaRNN
Benign
0.085
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
2.0
M
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-0.83
N
REVEL
Benign
0.065
Sift
Benign
0.057
T
Sift4G
Benign
0.55
T
Polyphen
0.013
B
Vest4
0.21
MVP
0.70
ClinPred
0.032
T
GERP RS
2.1
Varity_R
0.052
gMVP
0.41

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: rs556886570; hg19: chr20-42744958; API