PLCG2

protein-coding

phospholipase C gamma 2, the group of SH2 domain containing|C2 domain containing phospholipases|Phospholipases

Gene summary

The protein encoded by this gene is a transmembrane signaling enzyme that catalyzes the conversion of 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate to 1D-myo-inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) using calcium as a cofactor. IP3 and DAG are second messenger molecules important for transmitting signals from growth factor receptors and immune system receptors across the cell membrane. Mutations in this gene have been found in autoinflammation, antibody deficiency, and immune dysregulation syndrome and familial cold autoinflammatory syndrome 3. [provided by RefSeq, Mar 2014]

MANE transcript

NM_002661.5

Inheritance

ClinVar variants

P:11U:794B:487

Top phenotype

Familial cold autoinflammatory syndrome 3 (PLAID); Autoinflammation, antibody deficiency, and immune dysregulation syndrome (APLAID)

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr16:81,738,248-81,962,685

External References & Databases

Ensembl (ENSG00000197943)

Transcript & Mutation Effects

hg38 • Region Span ~224.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autoinflammation-PLCG2-associated antibody deficiency-immune dysregulationSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013944

Submitter: Ambry Genetics

familial cold autoinflammatory syndrome 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013766

Submitter: PanelApp Australia

familial cold autoinflammatory syndrome 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013766

Submitter: Labcorp Genetics (formerly Invitae)

autoinflammation-PLCG2-associated antibody deficiency-immune dysregulationSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013944

Submitter: Labcorp Genetics (formerly Invitae)

autoinflammation-PLCG2-associated antibody deficiency-immune dysregulationLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013944

Submitter: G2P

autoinflammation-PLCG2-associated antibody deficiency-immune dysregulationSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013944

Submitter: PanelApp Australia

familial cold autoinflammatory syndrome 3SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013766

Submitter: Orphanet

autoinflammation-PLCG2-associated antibody deficiency-immune dysregulationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013944

Submitter: Orphanet

familial cold autoinflammatory syndrome 3LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013766

Submitter: G2P

Clinical Genomic Database (CGD)

Familial cold autoinflammatory syndrome 3 (PLAID); Autoinflammation, antibody deficiency, and immune dysregulation syndrome (APLAID)AD

Manifestation: Allergy/Immunology/Infectious; Dermatologic

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals with Familial cold autoinflammatory syndrome 3 (PLAID) may be susceptible to recurrent and severe infections, and prophylaxis (eg, with IVIG) as well as early and aggressive treatment of infections may be beneficial; Individuals with APLAID may present with multi-system inflammation (eg, affecting the skin and GI system), and may demonstrate immune deficiency (eg, with frequent upper respiratory infections), and medical treatment (eg, with IL1 antagonists and high-dose corticosteroids) has been reported as beneficial

Refs: 19910034; 22236196; 23000145

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLCG2 variants in ClinVar

9 Conditions Cataloged

Familial cold autoinflammatory syndrome 3Total: 1562

not providedTotal: 258

Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulationTotal: 210

Inborn genetic diseasesTotal: 120

not specifiedTotal: 82

PLCG2-related disorderTotal: 58

Familial cold autoinflammatory syndromeTotal: 1

Recurrent feverTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002661.5. 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			11 clinvar	419 clinvar	7 clinvar	437
missense	2 clinvar	5 clinvar	751 clinvar	56 clinvar	5 clinvar	819
nonsense			12 clinvar			12
start loss						0
frameshift			7 clinvar			7
splice donor/acceptor (+/-2bp)	4 clinvar		13 clinvar			17
Total	6	5	794	475	12	1292

Highest pathogenic variant AF is 0.0000061956794

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 55 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002661.5	RefSeq	NP_002652.2	32	MANE Select
ENST00000564138.6	Ensembl	ENSP00000482457.1	32	MANE Select
NM_001425749.1	RefSeq	NP_001412678.1	32	Standard
NM_001425750.1	RefSeq	NP_001412679.1	32	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Inflammatory mediator regulation of TRP channels - Homo sapiens (human)
Non-small cell lung cancer - Homo sapiens (human)
Platelet activation - Homo sapiens (human)
B cell receptor signaling pathway - Homo sapiens (human)
Fc epsilon RI signaling pathway - Homo sapiens (human)

Biological Process

positive regulation of receptor internalization
stimulatory C-type lectin receptor signaling pathway
follicular B cell differentiation
phosphatidylinositol biosynthetic process
phospholipid catabolic process

Molecular Function

phosphotyrosine residue binding
phosphatidylinositol phospholipase C activity
phospholipase C activity
protein binding

Cellular Component

cytosol
plasma membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000359376
Coding exons: 32
Length: 219198
Individuals with no LoFs: 124788
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 124817
p: 0.000116

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.815	711	775	0.918	0.0000490	8399
Missense (PolyPhen)		167	270.77	0.61677		2878
Synonymous	-5.04	423	310	1.36	0.0000214	2269
Loss of Function	6.87	15	82.2	0.182	0.00000469	860

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00032	0.00032	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0	0.0	absent
Finnish	0.00019	0.00019	rare
European (Non-Finnish)	0.000097	0.000097	rare
South Asian	0.000066	0.000065	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes. It is a crucial enzyme in transmembrane signaling.;
Disease: DISEASE: Familial cold autoinflammatory syndrome 3 (FCAS3) [MIM:614468]: An autosomal dominant immune disorder characterized by the development of cutaneous urticaria, erythema, and pruritis in response to cold exposure. Affected individuals have variable additional immunologic defects, including antibody deficiency, decreased numbers of B-cells, defective B-cells, increased susceptibility to infection, and increased risk of autoimmune disorders. {ECO:0000269|PubMed:22236196}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Autoinflammation, antibody deficiency, and immune dysregulation PLCG2-associated (APLAID) [MIM:614878]: An autosomal dominant systemic disorder characterized by recurrent blistering skin lesions with a dense inflammatory infiltrate and variable involvement of other tissues, including joints, the eye, and the gastrointestinal tract. Affected individuals have a mild humoral immune deficiency associated with recurrent sinopulmonary infections, but no evidence of circulating autoantibodies. {ECO:0000269|PubMed:23000145}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.346

Intolerance Scores

LoFtool: 0.221
RVIS EVS: -0.6
RVIS percentile EVS: 17.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.549

Gene Damage Prediction

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