rs863225094

Variant names:

• chr19-52213076-G-A
• rs863225094
• NM_014225.6:c.773G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-52213076-G-A
• chr19-52213076-G-C
• chr19-52213076-G-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_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 (★★). Synonymous variant affecting the same amino acid position (i.e. R258R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP2R1A NM_014225.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.70
• Publications: 24 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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 217458.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.773G>A	p.Arg258His	missense	Exon 6 of 15	NP_055040.2
	PPP2R1A	NM_001363656.2		c.236G>A	p.Arg79His	missense	Exon 6 of 15	NP_001350585.1	B3KQV6
	PPP2R1A	NR_033500.2		n.717G>A		non_coding_transcript_exon	Exon 5 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R1A	ENST00000322088.11	TSL:1 MANE Select	c.773G>A	p.Arg258His	missense	Exon 6 of 15	ENSP00000324804.6	P30153
	PPP2R1A	ENST00000454220.7	TSL:1	c.893G>A	p.Arg298His	missense	Exon 6 of 15	ENSP00000391905.3	C9J9C1
	PPP2R1A	ENST00000703398.1		c.815G>A	p.Arg272His	missense	Exon 6 of 15	ENSP00000515288.1	A0A994J3H1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1445402 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718976

African (AFR) AF: 0.00 AC: 0 AN: 32944

American (AMR) AF: 0.00 AC: 0 AN: 42036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 84590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106894

Other (OTH) AF: 0.00 AC: 0 AN: 59772

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Houge-Janssens syndrome 2 (4)
4	-	-	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		8.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	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	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.88
gMVP		0.86
Mutation Taster		=3/97	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: rs863225094; hg19: chr19-52716329; COSMIC: COSV59042809; COSMIC: COSV59042809;