11-64926781-T-C

Position:

• chr11-64926781-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006244.4(PPP2R5B):​c.269T>C​(p.Phe90Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: PPP2R5B NM_006244.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.93

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R5B	NM_006244.4	c.269T>C	p.Phe90Ser	missense_variant	3/14	ENST00000164133.7	NP_006235.1
PPP2R5B	XM_047427199.1	c.269T>C	p.Phe90Ser	missense_variant	2/13		XP_047283155.1
PPP2R5B	XM_011545132.3	c.182T>C	p.Phe61Ser	missense_variant	4/15		XP_011543434.1
PPP2R5B	XM_047427200.1	c.182T>C	p.Phe61Ser	missense_variant	4/15		XP_047283156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R5B	ENST00000164133.7	c.269T>C	p.Phe90Ser	missense_variant	3/14	1	NM_006244.4	ENSP00000164133.2
PPP2R5B	ENST00000526559.5	c.269T>C	p.Phe90Ser	missense_variant	3/5	5		ENSP00000437088.1
PPP2R5B	ENST00000532850.1	c.11T>C	p.Phe4Ser	missense_variant	3/5	3		ENSP00000436136.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

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

Nov 03, 2022

The c.269T>C (p.F90S) alteration is located in exon 3 (coding exon 2) of the PPP2R5B gene. This alteration results from a T to C substitution at nucleotide position 269, causing the phenylalanine (F) at amino acid position 90 to be replaced by a serine (S). 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	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	4.2	.;H;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.3	D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.014	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.99
MutPred		0.88		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;
MVP		0.68
MPC		2.7
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.79
gMVP		0.95

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: chr11-64694253;