PPP1CB

protein-coding

protein phosphatase 1 catalytic subunit beta, the group of Protein phosphatase catalytic subunits

Gene summary

The protein encoded by this gene is one of the three catalytic subunits of protein phosphatase 1 (PP1). PP1 is a serine/threonine specific protein phosphatase known to be involved in the regulation of a variety of cellular processes, such as cell division, glycogen metabolism, muscle contractility, protein synthesis, and HIV-1 viral transcription. Mouse studies suggest that PP1 functions as a suppressor of learning and memory. Two alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002709.3

Inheritance

ClinVar variants

P:16U:101B:114

Top phenotype

Noonan syndrome-like disorder with loose anagen hair 2

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr2:28,751,640-28,802,940

External References & Databases

Ensembl (ENSG00000213639)

Transcript & Mutation Effects

hg38 • Region Span ~51.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Noonan syndrome-like disorder with loose anagen hairSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011899

Submitter: Orphanet

Noonan syndrome-like disorder with loose anagen hair 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054588

Submitter: Labcorp Genetics (formerly Invitae)

Noonan syndrome-like disorder with loose anagen hair 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0054588

Submitter: G2P

Noonan syndrome-like disorder with loose anagen hair 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054588

Submitter: Genomics England PanelApp

Noonan syndrome-like disorder with loose anagen hair 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054588

Submitter: PanelApp Australia

Noonan syndrome-like disorder with loose anagen hairDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011899

Submitter: ClinGen

PPP1CB was first reported in relation to autosomal dominant Noonan syndrome with loose anagen hair (AD NS-LAH) as early as 2016 (Gripp et al., PMID: 27264673). At least 4 unique missense variants (including the recurrent de novo p.Pro49Arg variant) have been reported in humans with this disorder. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 5 publications (PMID: 25356899, 27264673, 27681385, 27868344, 28211982). More evidence is available in the literature, but the maximum score for genetic evidence has been reached (PMID: 30236064). The mechanism of disease is thought to result in more stable/prolonged binding of SHOC2 and PPP1C to MRAS, which is expected to promote a more effective/prolonged RAF p.Ser259 dephosphorylation (PMID: 26446362, 23875798, 16630891). This gene-disease association is supported by relevant experimental evidence implicating a physical association of PP1c (of which PPP1CB is a subunit) with SHOC2, which is definitively associated with NS-LAH (PMID: 16630891, 24211266). The ClinGen RASopathy Expert Panel has assessed PPP1CB for associations with Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, and cardiofaciocutaneous syndrome, however no evidence was reported. In summary, PPP1CB is definitively associated with AD NS-LAH. This curation was approved by the ClinGen RASopathy Expert Panel on 4/23/20 (SOP Version 7).

Clinical Genomic Database (CGD)

Noonan syndrome-like disorder with loose anagen hair 2AD

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Genitourinary; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: Surveillance and treatment related to manifestations such as cardiac anomalies (which include pulmonic stenosis and valvular anomalies) can be beneficial

Refs: 25356899; 27264673; 27681385; 27868344; 28211982

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PPP1CB variants in ClinVar

12 Conditions Cataloged

not providedTotal: 295

Cardiovascular phenotypeTotal: 86

not specifiedTotal: 38

PPP1CB-related disorderTotal: 19

Noonan syndrome-like disorder with loose anagen hair 2Total: 17

RASopathyTotal: 7

Noonan syndromeTotal: 4

Inborn genetic diseasesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002709.3. 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			3 clinvar	112 clinvar	1 clinvar	116
missense	4 clinvar	12 clinvar	89 clinvar	1 clinvar		106
nonsense			3 clinvar			3
start loss						0
frameshift			5 clinvar			5
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	4	12	101	113	1	231

Highest pathogenic variant AF is 0.0000018603313

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 72 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002709.3	RefSeq	NP_002700.1	8	MANE Select
ENST00000395366.3	Ensembl	ENSP00000378769.2	8	MANE Select
NM_206876.2	RefSeq	NP_996759.1	8	Standard
ENST00000296122.10	Ensembl	ENSP00000296122.6	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ppp1cb	Danio rerio	Structure: whole organism Quality: shortened abnormal

Gene / Model

Organism

Observed Phenotype

ppp1cb

Danio rerio

Structure: whole organism

Quality: shortened

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Inflammatory mediator regulation of TRP channels - Homo sapiens (human)
Platelet activation - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)
Oxytocin signaling pathway - Homo sapiens (human)
Long-term potentiation - Homo sapiens (human)

Biological Process

glycogen metabolic process
protein dephosphorylation
cell cycle
regulation of cell adhesion
circadian regulation of gene expression

Molecular Function

protein serine/threonine phosphatase activity
protein binding
phosphatase activity
myosin phosphatase activity
protein kinase binding

Cellular Component

protein phosphatase type 1 complex
nuclear chromosome, telomeric region
nucleus
nucleoplasm
nucleolus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000395366
Coding exons: 8
Length: 51301
Individuals with no LoFs: 125711
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125714
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.33	17	181	0.0939	0.00000950	2132
Missense (PolyPhen)		1	77.35	0.012928		992
Synonymous	0.938	52	61.3	0.848	0.00000299	605
Loss of Function	4.18	0	20.4	0.00	0.00000130	237

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase (PP1) is essential for cell division, it participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Involved in regulation of ionic conductances and long-term synaptic plasticity. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. In balance with CSNK1D and CSNK1E, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. May dephosphorylate CSNK1D and CSNK1E. Dephosphorylates the 'Ser-418' residue of FOXP3 in regulatory T- cells (Treg) from patients with rheumatoid arthritis, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). {ECO:0000269|PubMed:20516061, ECO:0000269|PubMed:21712997, ECO:0000269|PubMed:23396208}.;
Disease: DISEASE: Noonan syndrome-like disorder with loose anagen hair 2 (NSLH2) [MIM:617506]: A syndrome characterized by Noonan dysmorphic features such as macrocephaly, high forehead, hypertelorism, palpebral ptosis, low-set and posteriorly rotated ears, short and webbed neck, pectus anomalies, in association with pluckable, sparse, thin and slow-growing hair. {ECO:0000269|PubMed:27264673, ECO:0000269|PubMed:27681385, ECO:0000269|PubMed:27868344, ECO:0000269|PubMed:28211982}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.222
RVIS EVS: -0.1
RVIS percentile EVS: 46.2

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.989

Gene Damage Prediction

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