4-6348005-C-G

Position:

• chr4-6348005-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020416.4(PPP2R2C):​c.631G>C​(p.Val211Leu) 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: 30)
• Consequence: PPP2R2C NM_020416.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.98

Genes affected

PPP2R2C (HGNC:9306): (protein phosphatase 2 regulatory subunit Bgamma) The product of this gene belongs to the phosphatase 2 regulatory subunit B family. 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 B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes a gamma isoform of the regulatory subunit B55 subfamily. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

PPP2R2C (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R2C	NM_020416.4	c.631G>C	p.Val211Leu	missense_variant	6/9	ENST00000382599.9	NP_065149.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R2C	ENST00000382599.9	c.631G>C	p.Val211Leu	missense_variant	6/9	1	NM_020416.4	ENSP00000372042.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2023

The c.631G>C (p.V211L) alteration is located in exon 6 (coding exon 6) of the PPP2R2C gene. This alteration results from a G to C substitution at nucleotide position 631, causing the valine (V) at amino acid position 211 to be replaced by a leucine (L). 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	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	.;.;.;T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;.;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.51	D;D;D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.1	M;.;.;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.7	D;D;D;D;D
REVEL	Benign	0.19
Sift	Benign	0.031	D;D;D;D;D
Sift4G	Benign	0.10	T;T;T;T;T
Polyphen		0.16	B;.;B;B;.
Vest4		0.88
MutPred		0.55		Gain of ubiquitination at K214 (P = 0.1693);.;.;Gain of ubiquitination at K214 (P = 0.1693);.;
MVP		0.50
MPC		1.3
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.54
gMVP		0.57

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: rs371827360; hg19: chr4-6349732;