rs368458529

Variant names:

• chr5-134225781-C-G
• NM_002715.4:c.81G>C

Your query was ambiguous. Multiple possible variants found:

• chr5-134225781-C-G
• chr5-134225781-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_002715.4(PPP2CA):​c.81G>C​(p.Gln27His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q27Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PPP2CA NM_002715.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.69

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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37558293).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2CA	NM_002715.4	c.81G>C	p.Gln27His	missense_variant	Exon 1 of 7	ENST00000481195.6	NP_002706.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2CA	ENST00000481195.6	c.81G>C	p.Gln27His	missense_variant	Exon 1 of 7	1	NM_002715.4	ENSP00000418447.1
ENSG00000272772	ENST00000519718.2	c.81G>C	p.Gln27His	missense_variant	Exon 1 of 6	5		ENSP00000430774.2
ENSG00000273345	ENST00000703317.1	n.*73+17111G>C		intron_variant	Intron 4 of 9			ENSP00000515260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457882 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725438

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	.;D
Eigen	Benign	0.033
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.8	.;M
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.26
Sift	Benign	0.037	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.0020	.;B
Vest4		0.70
MutPred		0.38		Loss of ubiquitination at K29 (P = 0.0504);Loss of ubiquitination at K29 (P = 0.0504);
MVP		0.38
MPC		0.64
ClinPred		0.98	D
GERP RS		4.2
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.59
gMVP		0.69

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: chr5-133561472;