19-52190176-T-C

Variant names:

• chr19-52190176-T-C
• ENST00000454220.7:c.80T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_014225.6(PPP2R1A):​c.78+2T>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPP2R1A NM_014225.6 splice_donor, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 5.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06949153 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R1A	NM_014225.6	c.78+2T>C		splice_donor_variant, intron_variant	Intron 1 of 14	ENST00000322088.11	NP_055040.2
PPP2R1A	NR_033500.2	n.123+2T>C		splice_donor_variant, intron_variant	Intron 1 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R1A	ENST00000322088.11	c.78+2T>C		splice_donor_variant, intron_variant	Intron 1 of 14	1	NM_014225.6	ENSP00000324804.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

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MutSpliceDB: a database of splice sites variants effects on splicing, NIH

Significance: not provided

Review Status: no classification provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	32
DANN	Uncertain	0.98
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Benign	0.67	D
ClinPred		0.67	D
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.92		Position offset: -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: chr19-52693429; COSMIC: COSV100436311;