chr19-52213076-G-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_014225.6(PPP2R1A):​c.773G>C​(p.Arg258Pro) 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. 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. R258H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2R1A NM_014225.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.70
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet, Illumina, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R1A	NM_014225.6	MANE Select	c.773G>C	p.Arg258Pro	missense	Exon 6 of 15	NP_055040.2
	PPP2R1A	NM_001363656.2		c.236G>C	p.Arg79Pro	missense	Exon 6 of 15	NP_001350585.1
	PPP2R1A	NR_033500.2		n.717G>C		non_coding_transcript_exon	Exon 5 of 14

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R1A	ENST00000322088.11	TSL:1 MANE Select	c.773G>C	p.Arg258Pro	missense	Exon 6 of 15	ENSP00000324804.6
	PPP2R1A	ENST00000454220.7	TSL:1	c.893G>C	p.Arg298Pro	missense	Exon 6 of 15	ENSP00000391905.3
	PPP2R1A	ENST00000703398.1		c.815G>C	p.Arg272Pro	missense	Exon 6 of 15	ENSP00000515288.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		8.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.69		Loss of MoRF binding (P = 5e-04)
MVP		0.84
MPC		3.2
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.99
gMVP		0.99
Mutation Taster		=6/94	disease causing

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;