PLCG2

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

Basic information

Region (hg38): 16:81738248-81962685

Links

ENSG00000197943 ∙ NCBI:5336 ∙ OMIM:600220 ∙ HGNC:9066 ∙ Uniprot:P16885 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation (Limited), mode of inheritance: AD
• familial cold autoinflammatory syndrome 3 (Limited), mode of inheritance: AD
• familial cold autoinflammatory syndrome 3 (Supportive), mode of inheritance: AD
• autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation (Supportive), mode of inheritance: AD
• autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation (Strong), mode of inheritance: AD
• familial cold autoinflammatory syndrome 3 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Familial cold autoinflammatory syndrome 3 (PLAID); Autoinflammation, antibody deficiency, and immune dysregulation syndrome (APLAID)	AD	Allergy/Immunology/Infectious	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	Allergy/Immunology/Infectious; Dermatologic	19910034; 22236196; 23000145

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PLCG2 gene.

• Familial cold autoinflammatory syndrome 3 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PLCG2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			6	338	13	357
missense	1	3	555	28	11	598
nonsense			10			10
start loss						0
frameshift			4			4
inframe indel			5			5
splice donor/acceptor (+/-2bp)			5			5
splice region			52	70	5	127
non coding			8	189	110	307
Total	1	3	593	555	134

Variants in PLCG2

This is a list of pathogenic ClinVar variants found in the PLCG2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
16-81785881-C-G		not specified	Benign (Jan 24, 2024)
16-81786000-C-T		Familial cold autoinflammatory syndrome 3	Likely benign (Oct 09, 2021)
16-81786001-G-A		Familial cold autoinflammatory syndrome 3	Likely benign (Jun 15, 2023)
16-81786001-G-C			Uncertain significance (Dec 30, 2022)
16-81786002-G-T		Familial cold autoinflammatory syndrome 3 • Inborn genetic diseases	Uncertain significance (Apr 26, 2023)
16-81786006-A-G		Familial cold autoinflammatory syndrome 3	Uncertain significance (Jan 20, 2023)
16-81786009-T-A		Inborn genetic diseases	Uncertain significance (Mar 29, 2024)
16-81786012-A-T		Familial cold autoinflammatory syndrome 3	Uncertain significance (Mar 29, 2023)
16-81786016-C-A		Familial cold autoinflammatory syndrome 3	Likely benign (Sep 16, 2022)
16-81786021-C-A		Familial cold autoinflammatory syndrome 3	Uncertain significance (Apr 13, 2023)
16-81786021-C-T		Familial cold autoinflammatory syndrome 3;Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation • Familial cold autoinflammatory syndrome 3 • Inborn genetic diseases	Uncertain significance (Aug 13, 2024)
16-81786031-G-A		Familial cold autoinflammatory syndrome 3	Likely benign (Sep 20, 2022)
16-81786035-A-G		Familial cold autoinflammatory syndrome 3	Uncertain significance (Mar 08, 2023)
16-81786037-C-G		Familial cold autoinflammatory syndrome 3 • Familial cold autoinflammatory syndrome 3;Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation	Uncertain significance (Aug 22, 2022)
16-81786037-C-T		Familial cold autoinflammatory syndrome 3	Likely benign (Oct 18, 2023)
16-81786039-A-G		Familial cold autoinflammatory syndrome 3	Uncertain significance (Sep 27, 2023)
16-81786039-A-T		Familial cold autoinflammatory syndrome 3	Uncertain significance (May 31, 2021)
16-81786046-G-A		Familial cold autoinflammatory syndrome 3 • Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation;Familial cold autoinflammatory syndrome 3	Benign/Likely benign (Jan 22, 2024)
16-81786048-G-A			Uncertain significance (Oct 01, 2019)
16-81786050-G-C		Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation	Uncertain significance (May 20, 2023)
16-81786050-G-T		Familial cold autoinflammatory syndrome 3	Uncertain significance (Aug 10, 2023)
16-81786051-C-T		Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation	Uncertain significance (-)
16-81786052-C-T		Familial cold autoinflammatory syndrome 3	Likely benign (Jun 11, 2023)
16-81786053-C-A		Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation	Uncertain significance (Mar 06, 2021)
16-81786061-G-C		Familial cold autoinflammatory syndrome 3	Likely benign (Oct 26, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PLCG2	protein_coding	protein_coding	ENST00000359376	32	219198

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.996	0.00438	124788	0	29	124817	0.000116

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.815	711	775	0.918	0.0000490	8399
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000410	0.000409
Ashkenazi Jewish	0.000199	0.000199
East Asian	0.00	0.00
Finnish	0.000186	0.000186
European (Non-Finnish)	0.0000972	0.0000971
Middle Eastern	0.00	0.00
South Asian	0.0000656	0.0000654
Other	0.000331	0.000330

dbNSFP

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.
• Pathway: 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);Fc gamma R-mediated phagocytosis - Homo sapiens (human);Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);Inositol phosphate metabolism - Homo sapiens (human);VEGF signaling pathway - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human);HIF-1 signaling pathway - Homo sapiens (human);ErbB signaling pathway - Homo sapiens (human);Epithelial cell signaling in Helicobacter pylori infection - Homo sapiens (human);Axon guidance - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Glioma - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);Vibrio cholerae infection - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);Natural killer cell mediated cytotoxicity - Homo sapiens (human);Phosphatidylinositol signaling system - Homo sapiens (human);Phospholipase D signaling pathway - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Osteoclast differentiation - Homo sapiens (human);NF-kappa B signaling pathway - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);EGFR Inhibitor Pathway, Pharmacodynamics;Leukocyte transendothelial migration - Homo sapiens (human);Proton Pump Inhibitor Pathway, Pharmacodynamics;Platelet Aggregation Inhibitor Pathway, Pharmacodynamics;VEGF Signaling Pathway;Leptin signaling pathway;Signaling Pathways in Glioblastoma;B Cell Receptor Signaling Pathway;Corticotropin-releasing hormone signaling pathway;Myometrial Relaxation and Contraction Pathways;GPR40 Pathway;Microglia Pathogen Phagocytosis Pathway;Ras Signaling;D-<i>myo</i>-inositol (1,4,5)-trisphosphate biosynthesis;Antigen activates B Cell Receptor (BCR) leading to generation of second messengers;DAP12 signaling;DAP12 interactions;B cell receptor signaling;Toll-Like Receptors Cascades;Dectin-2 family;Signaling by the B Cell Receptor (BCR);CD4 T cell receptor signaling-ERK cascade;CLEC7A (Dectin-1) signaling;Inositol phosphate metabolism;C-type lectin receptors (CLRs);Role of phospholipids in phagocytosis;Fcgamma receptor (FCGR) dependent phagocytosis;HGF;FCERI mediated MAPK activation;FCERI mediated Ca+2 mobilization;Fc epsilon receptor (FCERI) signaling;TCR;Innate Immune System;Immune System;Metabolism;FGF;phospholipases;Adaptive Immune System;D-<i>myo</i>-inositol-5-phosphate metabolism;superpathway of inositol phosphate compounds;BCR;CRH;GPVI-mediated activation cascade;Platelet activation, signaling and aggregation;EGFR1;Synthesis of IP3 and IP4 in the cytosol;Hemostasis;BCR signaling pathway;Inositol phosphate metabolism;Class I PI3K signaling events;IL4;EPO signaling pathway;Leptin;Toll Like Receptor 4 (TLR4) Cascade;VEGF;Nongenotropic Androgen signaling;CD4 T cell receptor signaling-JNK cascade;CD4 T cell receptor signaling-NFkB cascade;CD4 T cell receptor signaling (Consensus)

Recessive Scores

• pRec: 0.346

Intolerance Scores

• loftool: 0.221
• rvis_EVS: -0.6
• rvis_percentile_EVS: 17.92

Haploinsufficiency Scores

• pHI: 0.746
• hipred: Y
• hipred_score: 0.756
• ghis: 0.534

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.549

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Plcg2
• Phenotype: cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); neoplasm; limbs/digits/tail phenotype; immune system phenotype; skeleton phenotype; renal/urinary system phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype

Gene ontology

• Biological process: positive regulation of receptor internalization;stimulatory C-type lectin receptor signaling pathway;follicular B cell differentiation;phosphatidylinositol biosynthetic process;phospholipid catabolic process;regulation of gene expression;Wnt signaling pathway;calcium-mediated signaling;platelet activation;B cell differentiation;activation of store-operated calcium channel activity;positive regulation of type I interferon production;response to lipopolysaccharide;inositol trisphosphate biosynthetic process;Fc-epsilon receptor signaling pathway;Fc-gamma receptor signaling pathway involved in phagocytosis;negative regulation of programmed cell death;inositol phosphate metabolic process;phosphatidylinositol-mediated signaling;T cell receptor signaling pathway;B cell receptor signaling pathway;release of sequestered calcium ion into cytosol
• Cellular component: cytosol;plasma membrane;extracellular exosome
• Molecular function: phosphotyrosine residue binding;phosphatidylinositol phospholipase C activity;phospholipase C activity;protein binding