chr19-52190162-T-A

Variant names:

• chr19-52190162-T-A
• rs2122267837
• NM_014225.6:c.66T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014225.6(PPP2R1A):​c.66T>A​(p.Asn22Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPP2R1A NM_014225.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.518
• 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: Illumina, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.66T>A	p.Asn22Lys	missense	Exon 1 of 15	NP_055040.2
	PPP2R1A	NR_033500.2		n.111T>A		non_coding_transcript_exon	Exon 1 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R1A	ENST00000322088.11	TSL:1 MANE Select	c.66T>A	p.Asn22Lys	missense	Exon 1 of 15	ENSP00000324804.6	P30153
	PPP2R1A	ENST00000454220.7	TSL:1	c.66T>A	p.Asn22Lys	missense	Exon 1 of 15	ENSP00000391905.3	C9J9C1
	PPP2R1A	ENST00000703398.1		c.66T>A	p.Asn22Lys	missense	Exon 1 of 15	ENSP00000515288.1	A0A994J3H1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.00063
Eigen_PC	Benign	-0.075
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.099	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		0.52
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.17
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.016	D
Polyphen		0.77	P
Vest4		0.54
MutPred		0.62		Gain of ubiquitination at N22 (P = 0.0211)
MVP		0.71
MPC		2.0
ClinPred		0.99	D
GERP RS		1.2
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.73
gMVP		0.96
Mutation Taster		=38/162	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: rs2122267837; hg19: chr19-52693415;