chr19-52212726-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_014225.6(PPP2R1A):c.544C>T(p.Arg182Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
PPP2R1A
NM_014225.6 missense
NM_014225.6 missense
Scores
14
3
2
Clinical Significance
Conservation
PhyloP100: 3.10
Genes affected
PPP2R1A (HGNC:9302): (protein phosphatase 2 scaffold subunit Aalpha) This gene encodes a constant regulatory subunit of protein phosphatase 2. Protein phosphatase 2 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. The constant regulatory subunit A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. This gene encodes an alpha isoform of the constant regulatory subunit A. Alternatively spliced transcript variants have been described. [provided by RefSeq, Apr 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM1
In a region_of_interest SV40 small T antigen binding (size 154) in uniprot entity 2AAA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_014225.6
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PPP2R1A. . Gene score misZ: 4.4565 (greater than the threshold 3.09). Trascript score misZ: 5.4176 (greater than threshold 3.09). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. GenCC has associacion of the gene with intellectual disability, autosomal dominant 40, Houge-Janssens syndrome 2, complex neurodevelopmental disorder.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.925
PP5
Variant 19-52212726-C-T is Pathogenic according to our data. Variant chr19-52212726-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-52212726-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PPP2R1A | NM_014225.6 | c.544C>T | p.Arg182Trp | missense_variant | 5/15 | ENST00000322088.11 | NP_055040.2 | |
| PPP2R1A | NM_001363656.2 | c.7C>T | p.Arg3Trp | missense_variant | 5/15 | NP_001350585.1 | ||
| PPP2R1A | NR_033500.2 | n.488C>T | non_coding_transcript_exon_variant | 4/14 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Houge-Janssens syndrome 2 Pathogenic:5Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Oct 09, 2019 | This variant has been previously reported as a de novo change in multiple patients with intellectual disability, agenesis of the corpus callosum, and dysmorphic facies (PMID: 25533962, 26168268, 28628100). Cellular binding assays revealed that p.Arg182Trp affected PP2A holoenzyme formation, dephosphorylation dynamics, and link PP2A dysfunction to congenital brain dysfunction (PMID: 26168268). The variant is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. ClinVar contains an entry for the variant (Variation ID: 190312). The c.544C>T (p.Arg182Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.544C>T (p.Arg182Trp) variant is classified as Pathogenic. - |
| not provided, no classification provided | phenotyping only | GenomeConnect - Brain Gene Registry | - | Variant interpreted as Pathogenic and reported on 08-12-2019 by lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 03, 2015 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 03, 2019 | This variant was identified as de novo (maternity and paternity confirmed). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Nov 08, 2017 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 18, 2022 | Published functional studies demonstrate that R182W affects PP2A holoenzyme formation through the disruption of PR72 binding, which results in decreased PP2A phosphatase activity compared to wild type (PMID: 26168268); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28628100, 28867141, 28135719, 32565546, 31785789, 36209351, 36307859, 33057194, 36672867, 35982159, 33106617, 34958143, 25533962, 26168268) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 12, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 182 of the PPP2R1A protein (p.Arg182Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability and developmental delay (PMID: 25533962, 26168268). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 190312). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PPP2R1A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PPP2R1A function (PMID: 26168268). For these reasons, this variant has been classified as Pathogenic. - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2021 | The c.544C>T (p.R182W) alteration is located in coding exon 5 of the PPP2R1A gene. This alteration results from a C to T substitution at nucleotide position 544, causing the arginine (R) at amino acid position 182 to be replaced by a tryptophan (W). Based on data from the Genome Aggregation Database (gnomAD), the PPP2R1A c.544C>T alteration was not observed, with coverage at this position. This alteration has been reported to occur de novo in multiple unrelated patients with a neurodevelopmental disorder. Common clinical findings include developmental delay, lack of ambulation, hypotonia, anomalies of the corpus callosum, and epilepsy (Houge, 2015; Lenaerts, 2020). The p.R182 amino acid is conserved in available vertebrate species. Functional studies demonstrated in vitro that protein with this alteration had defective interaction and binding to other subunits of the PP2A holoenzyme, impairing the formation of PP2A, and decreasing the phosphatase activity of the enzyme (Houge, 2015; Lenaerts, 2020). The in silico prediction for the p.R182W alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
H;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.
REVEL
Uncertain
Sift
Pathogenic
D;.;.
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;.
Vest4
MutPred
Loss of disorder (P = 0.0344);.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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