chr19-52212729-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong

The NM_014225.6(PPP2R1A):​c.547C>T​(p.Arg183Trp) variant causes a missense change. 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

Scores

13
3
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 5.08
Variant links:
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). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, Houge-Janssens syndrome 2, complex neurodevelopmental disorder.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.859
PP5
Variant 19-52212729-C-T is Pathogenic according to our data. Variant chr19-52212729-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PPP2R1ANM_014225.6 linkuse as main transcriptc.547C>T p.Arg183Trp missense_variant 5/15 ENST00000322088.11 NP_055040.2
PPP2R1ANM_001363656.2 linkuse as main transcriptc.10C>T p.Arg4Trp missense_variant 5/15 NP_001350585.1
PPP2R1ANR_033500.2 linkuse as main transcriptn.491C>T non_coding_transcript_exon_variant 4/14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PPP2R1AENST00000322088.11 linkuse as main transcriptc.547C>T p.Arg183Trp missense_variant 5/151 NM_014225.6 ENSP00000324804 P4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Houge-Janssens syndrome 2 Pathogenic:2Other:1
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsDec 21, 2018This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. A nearby de novo missense variant c.544C>T(p.R182W) had been reported in 3 unrelated individuals with clinical features including hypoplasia or agenesis of corpus callosum, hypotonia and intellectual disability[PMID: 26168268] -
Likely pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologyApr 18, 2018ACMG codes: PS2, PM2, PP3 -
not provided, no classification providedphenotyping onlyGenomeConnect - Brain Gene Registry-Variant classified as Pathogenic and reported on 05-31-2023 by GeneDx. 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 Dr. Philip Payne 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/. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 02, 2023For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg183 amino acid residue in PPP2R1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PPP2R1A function (PMID: 33106617). 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. ClinVar contains an entry for this variant (Variation ID: 376505). This missense change has been observed in individual(s) with PPP2R1A-related conditions (PMID: 33106617, 34930662). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 183 of the PPP2R1A protein (p.Arg183Trp). -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 27, 2023Published functional studies demonstrate a damaging effect (impaired subunit binding) (PMID: 33106617); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34930662, 33106617) -
Prostate adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Malignant neoplasm of body of uterus Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Gastric adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Breast neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Lung adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Ovarian serous cystadenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Uterine carcinosarcoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Squamous cell carcinoma of the head and neck Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Neoplasm of the large intestine Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.080
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.93
D;.;.
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Benign
0.043
D
MetaRNN
Pathogenic
0.86
D;D;D
MetaSVM
Benign
-0.96
T
MutationAssessor
Pathogenic
4.0
H;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-7.6
D;.;.
REVEL
Uncertain
0.29
Sift
Pathogenic
0.0
D;.;.
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.80
MutPred
0.71
Loss of disorder (P = 0.0346);.;.;
MVP
0.69
MPC
2.7
ClinPred
1.0
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.9
Varity_R
0.98
gMVP
0.91

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: rs1057519946; hg19: chr19-52715982; COSMIC: COSV59042187; COSMIC: COSV59042187; API