chr5-134225806-T-TCGTTC

Variant names:

• chr5-134225806-T-TCGTTC
• NM_002715.4:c.51_55dupGAACG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002715.4(PPP2CA):​c.51_55dupGAACG​(p.Glu19GlyfsTer23) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E19E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2CA NM_002715.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.98

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 41 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-134225806-T-TCGTTC is Pathogenic according to our data. Variant chr5-134225806-T-TCGTTC is described in ClinVar as [Pathogenic]. Clinvar id is 1382033.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2CA	NM_002715.4	c.51_55dupGAACG	p.Glu19GlyfsTer23	frameshift_variant	Exon 1 of 7	ENST00000481195.6	NP_002706.1
MIR3661	NR_037434.1	n.51_55dupCGTTC		non_coding_transcript_exon_variant	Exon 1 of 1
MIR3661	unassigned_transcript_863	n.*8_*9insCGTTC		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2CA	ENST00000481195.6	c.51_55dupGAACG	p.Glu19GlyfsTer23	frameshift_variant	Exon 1 of 7	1	NM_002715.4	ENSP00000418447.1
ENSG00000272772	ENST00000519718.2	c.51_55dupGAACG	p.Glu19GlyfsTer43	frameshift_variant	Exon 1 of 6	5		ENSP00000430774.2
ENSG00000273345	ENST00000703317.1	n.*73+17081_*73+17085dupGAACG		intron_variant	Intron 4 of 9			ENSP00000515260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Sep 17, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu19Glyfs*23) in the PPP2CA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PPP2CA are known to be pathogenic (PMID: 30595372). This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PPP2CA-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr5-133561497;