rs764474492
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_020433.5(JPH2):āc.226A>Gā(p.Thr76Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,613,820 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 ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 31)
Exomes š: 0.000018 ( 0 hom. )
Consequence
JPH2
NM_020433.5 missense
NM_020433.5 missense
Scores
8
11
Clinical Significance
Conservation
PhyloP100: 5.93
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.27510983).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JPH2 | NM_020433.5 | c.226A>G | p.Thr76Ala | missense_variant | 1/6 | ENST00000372980.4 | |
JPH2 | NM_175913.4 | c.226A>G | p.Thr76Ala | missense_variant | 1/2 | ||
JPH2 | XM_006723833.5 | c.226A>G | p.Thr76Ala | missense_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JPH2 | ENST00000372980.4 | c.226A>G | p.Thr76Ala | missense_variant | 1/6 | 5 | NM_020433.5 | P1 | |
JPH2 | ENST00000342272.3 | c.226A>G | p.Thr76Ala | missense_variant | 1/2 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151950Hom.: 0 Cov.: 31
GnomAD3 genomes
?
AF:
AC:
2
AN:
151950
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251290Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135788
GnomAD3 exomes
AF:
AC:
4
AN:
251290
Hom.:
AF XY:
AC XY:
3
AN XY:
135788
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461870Hom.: 0 Cov.: 65 AF XY: 0.0000220 AC XY: 16AN XY: 727238
GnomAD4 exome
AF:
AC:
26
AN:
1461870
Hom.:
Cov.:
65
AF XY:
AC XY:
16
AN XY:
727238
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151950Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74218
GnomAD4 genome
?
AF:
AC:
2
AN:
151950
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
74218
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
?
AF:
AC:
1
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 submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 20, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 08, 2017 | A variant of uncertain significance has been identified in the JPH2 gene. The T76A variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T76A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this variant has not been observed in a significant number of affected individuals, and it lacks both segregation and functional studies, which would further clarify its pathogenicity. - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2022 | Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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. ClinVar contains an entry for this variant (Variation ID: 451220). This variant has not been reported in the literature in individuals affected with JPH2-related conditions. This variant is present in population databases (rs764474492, gnomAD 0.004%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 76 of the JPH2 protein (p.Thr76Ala). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Uncertain
D;T
Sift4G
Uncertain
D;T
Polyphen
D;B
Vest4
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at