rs786205227

Variant names:

• chr19-52212726-C-T
• rs786205227
• NM_014225.6:c.544C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-52212726-C-T
• chr19-52212726-C-G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PM5 PP3_Moderate PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV001445875: Cellular binding assays revealed that p.Arg182Trp affected PP2A holoenzyme formation, dephosphorylation dynamics, and link PP2A dysfunction to congenital brain dysfunction (PMID:26168268)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R182Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2R1A NM_014225.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 3.10
• Publications: 32 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001445875: Cellular binding assays revealed that p.Arg182Trp affected PP2A holoenzyme formation, dephosphorylation dynamics, and link PP2A dysfunction to congenital brain dysfunction (PMID: 26168268).; SCV000491305: 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); SCV001585609: Experimental studies have shown that this missense change affects PPP2R1A function (PMID: 26168268).; SCV003678861: 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).
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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 chr19-52212727-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3649140.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 190312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R1A	NM_014225.6	MANE Select	c.544C>T	p.Arg182Trp	missense	Exon 5 of 15	NP_055040.2
	PPP2R1A	NM_001363656.2		c.7C>T	p.Arg3Trp	missense	Exon 5 of 15	NP_001350585.1	B3KQV6
	PPP2R1A	NR_033500.2		n.488C>T		non_coding_transcript_exon	Exon 4 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R1A	ENST00000322088.11	TSL:1 MANE Select	c.544C>T	p.Arg182Trp	missense	Exon 5 of 15	ENSP00000324804.6	P30153
	PPP2R1A	ENST00000454220.7	TSL:1	c.664C>T	p.Arg222Trp	missense	Exon 5 of 15	ENSP00000391905.3	C9J9C1
	PPP2R1A	ENST00000703398.1		c.586C>T	p.Arg196Trp	missense	Exon 5 of 15	ENSP00000515288.1	A0A994J3H1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Houge-Janssens syndrome 2 (7)
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Pathogenic	4.0	H
PhyloP100		3.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.6	D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.84		Loss of disorder (P = 0.0344)
MVP		0.91
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		0.97
gMVP		0.97
Mutation Taster		=14/86	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786205227; hg19: chr19-52715979; COSMIC: COSV59042121; COSMIC: COSV59042121;