11-64925753-C-T

Variant names:

• chr11-64925753-C-T
• rs199949257
• NM_006244.4:c.19C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006244.4(PPP2R5B):​c.19C>T​(p.Pro7Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000332 in 1,594,284 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000036 (1 hom.)
• Consequence: PPP2R5B NM_006244.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.89

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06627905).
• BS2: High AC in GnomAdExome4 at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R5B	NM_006244.4	c.19C>T	p.Pro7Ser	missense_variant	Exon 2 of 14	ENST00000164133.7	NP_006235.1
PPP2R5B	XM_047427199.1	c.19C>T	p.Pro7Ser	missense_variant	Exon 1 of 13		XP_047283155.1
PPP2R5B	XM_011545132.3	c.27-95C>T		intron_variant	Intron 2 of 14		XP_011543434.1
PPP2R5B	XM_047427200.1	c.27-95C>T		intron_variant	Intron 2 of 14		XP_047283156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R5B	ENST00000164133.7	c.19C>T	p.Pro7Ser	missense_variant	Exon 2 of 14	1	NM_006244.4	ENSP00000164133.2
PPP2R5B	ENST00000526559.5	c.19C>T	p.Pro7Ser	missense_variant	Exon 2 of 5	5		ENSP00000437088.1
PPP2R5B	ENST00000532850.1	c.-145-95C>T		intron_variant	Intron 1 of 4	3		ENSP00000436136.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152064 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000584 AC: 13 AN: 222734 Hom.: 0 AF XY: 0.0000653 AC XY: 8 AN XY: 122436

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000766

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000361 AC: 52 AN: 1442102 Hom.: 1 Cov.: 29 AF XY: 0.0000349 AC XY: 25 AN XY: 716990

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00131

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.09e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 29 AF XY: 0.0000134 AC XY: 1 AN XY: 74404

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000415 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

PPP2R5B-related disorder Uncertain:1

Jan 09, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PPP2R5B c.19C>T variant is predicted to result in the amino acid substitution p.Pro7Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.077% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-64693225-C-T), which is more common than expected for a disease gene with a dominant mode of inheritnace, as has been proposed for PPP2R5B. Although we suspect that this variant may be benign, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.066	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.5	.;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.75	N;N
REVEL	Benign	0.21
Sift	Benign	0.094	T;T
Sift4G	Benign	0.67	T;T
Polyphen		0.91	.;P
Vest4		0.36
MVP		0.24
MPC		0.19
ClinPred		0.19	T
GERP RS		3.5
Varity_R		0.037
gMVP		0.45

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: rs199949257; hg19: chr11-64693225;