chr19-52190170-T-C

Variant names:

• chr19-52190170-T-C
• NM_014225.6:c.74T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_014225.6(PPP2R1A):​c.74T>C​(p.Val25Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V25F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPP2R1A NM_014225.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.18
• 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 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_014225.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40920314).

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.74T>C	p.Val25Ala	missense	Exon 1 of 15	NP_055040.2
	PPP2R1A	NR_033500.2		n.119T>C		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.74T>C	p.Val25Ala	missense	Exon 1 of 15	ENSP00000324804.6	P30153
	PPP2R1A	ENST00000454220.7	TSL:1	c.74T>C	p.Val25Ala	missense	Exon 1 of 15	ENSP00000391905.3	C9J9C1
	PPP2R1A	ENST00000703398.1		c.74T>C	p.Val25Ala	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, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	0.087
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.2
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.044	D
Polyphen		0.018	B
Vest4		0.59
MutPred		0.41		Gain of disorder (P = 0.0666)
MVP		0.66
MPC		1.6
ClinPred		0.97	D
GERP RS		5.0
PromoterAI		0.0015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.51
gMVP		0.84
Mutation Taster		=35/65	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

hg19: chr19-52693423;