11-64926885-G-C

Position:

• chr11-64926885-G-C

Variant summary

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

The NM_006244.4(PPP2R5B):​c.373G>C​(p.Val125Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPP2R5B NM_006244.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

Genes affected

PPP2R5B (HGNC:9310): (protein phosphatase 2 regulatory subunit B'beta) The product of this gene belongs to the phosphatase 2A regulatory subunit B family. 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. The B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes a beta isoform of the regulatory subunit B56 subfamily. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29369822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R5B	NM_006244.4	c.373G>C	p.Val125Leu	missense_variant	3/14	ENST00000164133.7	NP_006235.1
PPP2R5B	XM_047427199.1	c.373G>C	p.Val125Leu	missense_variant	2/13		XP_047283155.1
PPP2R5B	XM_011545132.3	c.286G>C	p.Val96Leu	missense_variant	4/15		XP_011543434.1
PPP2R5B	XM_047427200.1	c.286G>C	p.Val96Leu	missense_variant	4/15		XP_047283156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R5B	ENST00000164133.7	c.373G>C	p.Val125Leu	missense_variant	3/14	1	NM_006244.4	ENSP00000164133.2
PPP2R5B	ENST00000526559.5	c.373G>C	p.Val125Leu	missense_variant	3/5	5		ENSP00000437088.1
PPP2R5B	ENST00000532850.1	c.115G>C	p.Val39Leu	missense_variant	3/5	3		ENSP00000436136.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2023

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 125 of the PPP2R5B protein (p.Val125Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PPP2R5B-related conditions. ClinVar contains an entry for this variant (Variation ID: 2055431). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PPP2R5B protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;T;T
Eigen	Benign	-0.090
Eigen_PC	Benign	0.034
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.85	D;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.91	.;L;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.046
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.010	.;B;.
Vest4		0.16
MutPred		0.42		Gain of catalytic residue at V125 (P = 0.0516);Gain of catalytic residue at V125 (P = 0.0516);.;
MVP		0.33
MPC		0.95
ClinPred		0.44	T
GERP RS		3.9
Varity_R		0.10
gMVP		0.34

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: chr11-64694357;