Genetic Variant PPP2R1A:p.Pro179Arg (chr19-52212718-C-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_014225.6(PPP2R1A):c.536C>G(p.Pro179Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P179H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PPP2R1A
NM_014225.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.92

Publications

62 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Houge-Janssens syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, Labcorp Genetics (formerly Invitae), G2P

PPP2R1A links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_014225.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-52212718-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1699184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014225.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPP2R1A	NM_014225.6	MANE Select	c.536C>G	p.Pro179Arg	missense	Exon 5 of 15	NP_055040.2
PPP2R1A	NM_001363656.2		c.-2C>G		5_prime_UTR	Exon 5 of 15	NP_001350585.1	B3KQV6
PPP2R1A	NR_033500.2		n.480C>G		non_coding_transcript_exon	Exon 4 of 14

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPP2R1A	ENST00000322088.11	TSL:1 MANE Select	c.536C>G	p.Pro179Arg	missense	Exon 5 of 15	ENSP00000324804.6	P30153
PPP2R1A	ENST00000454220.7	TSL:1	c.656C>G	p.Pro219Arg	missense	Exon 5 of 15	ENSP00000391905.3	C9J9C1
PPP2R1A	ENST00000703398.1		c.578C>G	p.Pro193Arg	missense	Exon 5 of 15	ENSP00000515288.1	A0A994J3H1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.083

MetaRNN

Pathogenic

0.90

MetaSVM

Benign

-0.48

MutationAssessor

Pathogenic

4.0

PhyloP100

6.9

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-8.5

REVEL

Uncertain

0.39

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.87

MutPred

0.76

Gain of MoRF binding (P = 2e-04)

MVP

0.75

MPC

2.7

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.98

gMVP

0.92

Mutation Taster

=19/81

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over