Variant 5-146592977-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_181675.4(PPP2R2B):c.1046C>T(p.Ser349Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000213 in 1,458,358 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

PPP2R2B
NM_181675.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.71

Variant links:

Genes affected

PPP2R2B (HGNC:9305): (protein phosphatase 2 regulatory subunit Bbeta) 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 beta isoform of the regulatory subunit B55 subfamily. Defects in this gene cause autosomal dominant spinocerebellar ataxia 12 (SCA12), a disease caused by degeneration of the cerebellum, sometimes involving the brainstem and spinal cord, and in resulting in poor coordination of speech and body movements. Multiple alternatively spliced variants, which encode different isoforms, have been identified for this gene. The 5' UTR of some of these variants includes a CAG trinucleotide repeat sequence (7-28 copies) that can be expanded to 55-78 copies in cases of SCA12. [provided by RefSeq, Jul 2016]

PPP2R2B links:

PPP2R2B (HGNC:):

PPP2R2B links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PPP2R2B. . Gene score misZ 2.2458 (greater than the threshold 3.09). Trascript score misZ 3.5161 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia type 12.

BS2

High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R2B	NM_181675.4 linkuse as main transcript	c.1046C>T	p.Ser349Leu	missense_variant	9/10	ENST00000394411.9	NP_858061.3	Q00005-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R2B	ENST00000394411.9 linkuse as main transcript	c.1046C>T	p.Ser349Leu	missense_variant	9/10	2	NM_181675.4	ENSP00000377933.3		Q00005-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251202

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000213

AC:

AN:

1458358

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

725742

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000271

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2023

The c.1055C>T (p.S352L) alteration is located in exon 8 (coding exon 8) of the PPP2R2B gene. This alteration results from a C to T substitution at nucleotide position 1055, causing the serine (S) at amino acid position 352 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

Benign

0.14

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;.;.;D;.;.;.;.

Eigen

Benign

0.19

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;.;D;D;D;D;D;D

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.59

D;D;D;D;D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

M;.;.;M;.;.;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.7

.;D;D;D;.;D;D;.

REVEL

Benign

0.23

Sift

Uncertain

0.0010

.;D;D;D;.;D;D;.

Sift4G

Uncertain

0.0020

D;D;D;D;D;D;D;D

Polyphen

0.022

B;.;B;B;.;B;B;B

Vest4

0.74

MutPred

0.40

Loss of catalytic residue at M354 (P = 0.1002);.;.;Loss of catalytic residue at M354 (P = 0.1002);.;.;.;.;

MVP

0.66

MPC

0.66

ClinPred

0.94

GERP RS

5.3

Varity_R

0.51

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over