rs368458529

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_002715.4(PPP2CA):​c.81G>C​(p.Gln27His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q27Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

PPP2CA
NM_002715.4 missense

Scores

2
7
9

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.69
Variant links:
Genes affected
PPP2CA (HGNC:9299): (protein phosphatase 2 catalytic subunit alpha) This gene encodes the phosphatase 2A catalytic subunit. Protein phosphatase 2A is one of the four major Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. This gene encodes an alpha isoform of the catalytic subunit. [provided by RefSeq, Jul 2008]
MIR3661 (HGNC:38892): (microRNA 3661) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the PPP2CA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 4.1504 (above the threshold of 3.09). Trascript score misZ: 5.562 (above the threshold of 3.09). GenCC associations: The gene is linked to Houge-Janssens syndrome 3.
BP4
Computational evidence support a benign effect (MetaRNN=0.37558293).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PPP2CANM_002715.4 linkc.81G>C p.Gln27His missense_variant Exon 1 of 7 ENST00000481195.6 NP_002706.1 P67775-1B3KUN1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PPP2CAENST00000481195.6 linkc.81G>C p.Gln27His missense_variant Exon 1 of 7 1 NM_002715.4 ENSP00000418447.1 P67775-1
ENSG00000272772ENST00000519718.2 linkc.81G>C p.Gln27His missense_variant Exon 1 of 6 5 ENSP00000430774.2 E5RI56
ENSG00000273345ENST00000703317.1 linkn.*73+17111G>C intron_variant Intron 4 of 9 ENSP00000515260.1 A0A8V8TQA6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1457882
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
725438
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.010
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.53
.;D
Eigen
Benign
0.033
Eigen_PC
Benign
0.13
FATHMM_MKL
Benign
0.65
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Pathogenic
0.66
D
MetaRNN
Benign
0.38
T;T
MetaSVM
Benign
-0.82
T
MutationAssessor
Uncertain
2.8
.;M
PROVEAN
Benign
-1.5
N;N
REVEL
Benign
0.26
Sift
Benign
0.037
D;D
Sift4G
Uncertain
0.013
D;D
Polyphen
0.0020
.;B
Vest4
0.70
MutPred
0.38
Loss of ubiquitination at K29 (P = 0.0504);Loss of ubiquitination at K29 (P = 0.0504);
MVP
0.38
MPC
0.64
ClinPred
0.98
D
GERP RS
4.2
RBP_binding_hub_radar
1.0
RBP_regulation_power_radar
2.8
Varity_R
0.59
gMVP
0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-133561472; API