5-134199126-C-T

Position:

• chr5-134199126-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_002715.4(PPP2CA):​c.817G>A​(p.Ala273Thr) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2CA NM_002715.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.56

Genes affected

PPP2CA (HGNC:9299): (protein phosphatase 2 catalytic subunit alpha) This gene encodes the phosphatase 2A catalytic subunit. Protein phosphatase 2A 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. This gene encodes an alpha isoform of the catalytic subunit. [provided by RefSeq, Jul 2008]

ENSG00000272772 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PPP2CA. . Gene score misZ 4.1504 (greater than the threshold 3.09). Trascript score misZ 5.562 (greater than threshold 3.09). GenCC has associacion of gene with Houge-Janssens syndrome 3.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2CA	NM_002715.4	c.817G>A	p.Ala273Thr	missense_variant	6/7	ENST00000481195.6	NP_002706.1
PPP2CA	NM_001355019.2	c.622G>A	p.Ala208Thr	missense_variant	6/7		NP_001341948.1
PPP2CA	NR_149151.2	n.1072G>A		non_coding_transcript_exon_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2CA	ENST00000481195.6	c.817G>A	p.Ala273Thr	missense_variant	6/7	1	NM_002715.4	ENSP00000418447.1
ENSG00000272772	ENST00000519718.2	c.103-25104G>A		intron_variant		5		ENSP00000430774.2
ENSG00000273345	ENST00000703317.1	n.*788G>A		non_coding_transcript_exon_variant	9/10			ENSP00000515260.1
ENSG00000273345	ENST00000703317.1	n.*788G>A		3_prime_UTR_variant	9/10			ENSP00000515260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Houge-Janssens syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Apr 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Pathogenic	4.5	H
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.54	P
Vest4		0.90
MutPred		0.80		Gain of sheet (P = 0.0827);
MVP		0.78
MPC		1.8
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.75
gMVP		0.96

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-133534817;