rs863225094

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP2PP3PP5_Very_Strong

The NM_014225.6(PPP2R1A):c.773G>A(p.Arg258His) 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PPP2R1A
NM_014225.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 8.70

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 Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the PPP2R1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 4.4565 (above the threshold of 3.09). Trascript score misZ: 5.4176 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 40, Houge-Janssens syndrome 2, complex neurodevelopmental disorder.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.769

PP5

Variant 19-52213076-G-A is Pathogenic according to our data. Variant chr19-52213076-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-52213076-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R1A	NM_014225.6 link	c.773G>A	p.Arg258His	missense_variant	Exon 6 of 15	ENST00000322088.11	NP_055040.2	P30153A8K7B7
PPP2R1A	NM_001363656.2 link	c.236G>A	p.Arg79His	missense_variant	Exon 6 of 15		NP_001350585.1
PPP2R1A	NR_033500.2 link	n.717G>A		non_coding_transcript_exon_variant	Exon 5 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R1A	ENST00000322088.11 link	c.773G>A	p.Arg258His	missense_variant	Exon 6 of 15	1	NM_014225.6	ENSP00000324804.6		P30153

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1445402

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718976

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Houge-Janssens syndrome 2

Pathogenic:4

Dec 30, 2019

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

[ACMG/AMP: PS2, PS3_Moderate, PM2, PP3] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3_Moderate], is absent from or rarely observed in large-scale population databases [PM2], is predicted to be damaging by multiple functional prediction tools [PP3]. -

Aug 03, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (ClinVar ID: VCV000217458.5, PMID: 26168268, 33106617, and 30755392, PS2 and PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Jan 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 258 of the PPP2R1A protein (p.Arg258His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability syndrome (PMID: 26168268, 30755392, 32901917, 33106617). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 217458). 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. Experimental studies have shown that this missense change affects PPP2R1A function (PMID: 26168268). For these reasons, this variant has been classified as Pathogenic. -

May 20, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies showed R258H causes impaired binding between the A and B subunits of PP2A and decreases PP2A phosphatase activity (Houge et al., 2015; Lenaerts et al., 2020); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26197069, 26168268, 27485451, 27294619, 33106617, 32901917, 30755392) -

Nov 19, 2018

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Benign

0.049

MetaRNN

Pathogenic

0.77

D;D;D

MetaSVM

Benign

-0.90

MutationAssessor

Pathogenic

4.1

H;.;.

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-4.9

D;.;.

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

D;.;.

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.82

MutPred

0.59

Loss of MoRF binding (P = 0.0056);.;.;

MVP

0.71

MPC

2.9

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.88

gMVP

0.86

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.

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