rs1057519947

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5

The NM_014225.6(PPP2R1A):c.548G>A(p.Arg183Gln) variant causes a missense change involving the alteration of a 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

PPP2R1A
NM_014225.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12U:1O:1

Conservation

PhyloP100: 8.72

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]

PPP2R1A links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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, 0.809

PP5

Variant 19-52212730-G-A is Pathogenic according to our data. Variant chr19-52212730-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 376506.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, not_provided=1, Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PPP2R1A	NM_014225.6 linkuse as main transcript	c.548G>A	p.Arg183Gln	missense_variant	5/15	ENST00000322088.11	NP_055040.2
PPP2R1A	NM_001363656.2 linkuse as main transcript	c.11G>A	p.Arg4Gln	missense_variant	5/15		NP_001350585.1
PPP2R1A	NR_033500.2 linkuse as main transcript	n.492G>A		non_coding_transcript_exon_variant	4/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R1A	ENST00000322088.11 linkuse as main transcript	c.548G>A	p.Arg183Gln	missense_variant	5/15	1	NM_014225.6	ENSP00000324804	P4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 31, 2021	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. This variant has been observed in individual(s) with clinical features of PPP2R1A-related intellectual disability (PMID: 31687265, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376506). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 183 of the PPP2R1A protein (p.Arg183Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2023	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21381030, 23267135, 21435433, 26619011, 31687265, 35584285, 34958143) -

Houge-Janssens syndrome 2

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Feb 06, 2020	- -

Prostate adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant neoplasm of body of uterus

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gastric adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast neoplasm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Ovarian serous cystadenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Uterine carcinosarcoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of the large intestine

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the head and neck

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Intellectual disability

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Brain Gene Registry

Variant interpreted as Pathogenic and reported on 10-15-2020 by Lab or GTR ID 26957. Variant found to be mosaic in participant. 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/. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;.;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.81

D;D;D

MetaSVM

Benign

-0.82

MutationAssessor

Pathogenic

4.0

H;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.8

D;.;.

REVEL

Uncertain

0.31

Sift

Uncertain

0.0010

D;.;.

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.68

MutPred

0.62

Loss of ubiquitination at K188 (P = 0.0716);.;.;

MVP

0.74

MPC

2.8

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.95

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over