PPP2R2B

protein-coding

protein phosphatase 2 regulatory subunit Bbeta, the group of WD repeat domain containing|Protein phosphatase 2 regulatory subunits

Gene summary

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]

Previous symbols:

SCA12

MANE transcript

NM_181675.4

Inheritance

ClinVar variants

U:68B:13

Top phenotype

Spinocerebellar ataxia 12

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr5:146,580,742-147,084,784

External References & Databases

Ensembl (ENSG00000156475)

Transcript & Mutation Effects

hg38 • Region Span ~504.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia type 12SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011439

Submitter: Orphanet

spinocerebellar ataxia type 12MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011439

Submitter: Ambry Genetics

spinocerebellar ataxia type 12STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011439

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Spinocerebellar ataxia 12AD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: The condition involves expansion of triplet repeats

Refs: 10581021; 11719278; 14526180; 16138911; 20301381; 20629122

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PPP2R2B variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 42

not providedTotal: 35

Spinocerebellar ataxia type 12Total: 6

PPP2R2B-related disorderTotal: 5

Neurodevelopmental disorderTotal: 1

Global developmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_181675.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	6 clinvar		7
missense			63 clinvar	7 clinvar		70
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	68	13	0	81

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_181675.4	RefSeq	NP_858061.3	9	MANE Select
ENST00000394411.9	Ensembl	ENSP00000377933.3	9	MANE Select
NM_001271899.1	RefSeq	NP_001258828.1	10	Standard
NM_001271900.2	RefSeq	NP_001258829.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Dopaminergic synapse - Homo sapiens (human)
Tight junction - Homo sapiens (human)
mRNA surveillance pathway - Homo sapiens (human)
AMPK signaling pathway - Homo sapiens (human)

Biological Process

mitotic cell cycle
apoptotic process
regulation of phosphoprotein phosphatase activity
peptidyl-serine dephosphorylation

Molecular Function

protein serine/threonine phosphatase activity
protein binding
protein phosphatase regulator activity

Cellular Component

protein phosphatase type 2A complex
mitochondrion
mitochondrial outer membrane
cytosol
cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000336640
Coding exons: 9
Length: 496412
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125747
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.25	167	271	0.616	0.0000159	3004
Missense (PolyPhen)		28	84.741	0.33042		988
Synonymous	0.447	96	102	0.944	0.00000615	812
Loss of Function	3.90	2	21.5	0.0930	0.00000119	245

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The B regulatory subunit might modulate substrate selectivity and catalytic activity, and also might direct the localization of the catalytic enzyme to a particular subcellular compartment. Within the PP2A holoenzyme complex, isoform 2 is required to promote proapoptotic activity (By similarity). Isoform 2 regulates neuronal survival through the mitochondrial fission and fusion balance (By similarity). {ECO:0000250}.;
Disease: DISEASE: Spinocerebellar ataxia 12 (SCA12) [MIM:604326]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA12 is an autosomal dominant cerebellar ataxia (ADCA). {ECO:0000269|PubMed:10581021}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.246

Intolerance Scores

LoFtool: 0.720
RVIS EVS: -0.74
RVIS percentile EVS: 13.94

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.866

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium