5-134225819-C-T

Variant names:

• chr5-134225819-C-T
• rs2081664656
• NM_002715.4:c.43G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_002715.4(PPP2CA):​c.43G>A​(p.Glu15Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 5.39

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:):

MIR3661 (HGNC:38892): (microRNA 3661) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PPP2CA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 4.1504 (above the threshold of 3.09). Trascript score misZ: 5.562 (above the threshold of 3.09). GenCC associations: The gene is linked to Houge-Janssens syndrome 3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2CA	NM_002715.4	c.43G>A	p.Glu15Lys	missense_variant	Exon 1 of 7	ENST00000481195.6	NP_002706.1
MIR3661	NR_037434.1	n.63C>T		non_coding_transcript_exon_variant	Exon 1 of 1
MIR3661	unassigned_transcript_863	n.*21C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2CA	ENST00000481195.6	c.43G>A	p.Glu15Lys	missense_variant	Exon 1 of 7	1	NM_002715.4	ENSP00000418447.1
ENSG00000272772	ENST00000519718.2	c.43G>A	p.Glu15Lys	missense_variant	Exon 1 of 6	5		ENSP00000430774.2
ENSG00000273345	ENST00000703317.1	n.*73+17073G>A		intron_variant	Intron 4 of 9			ENSP00000515260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.43G>A (p.E15K) alteration is located in exon 1 (coding exon 1) of the PPP2CA gene. This alteration results from a G to A substitution at nucleotide position 43, causing the glutamic acid (E) at amino acid position 15 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	0.0080	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	.;D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.7	.;M
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.24
Sift	Benign	0.052	T;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.018	.;B
Vest4		0.60
MutPred		0.41		Gain of methylation at E15 (P = 0.0101);Gain of methylation at E15 (P = 0.0101);
MVP		0.29
MPC		0.76
ClinPred		0.96	D
GERP RS		5.1
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.69
gMVP		0.68

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

LitVar

Other links and lift over

dbSNP: rs2081664656; hg19: chr5-133561510;