RAG2

recombination activating 2

Basic information

Region (hg38): 11:36575574-36598279

Links

ENSG00000175097 ∙ NCBI:5897 ∙ OMIM:179616 ∙ HGNC:9832 ∙ Uniprot:P55895 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Omenn syndrome (Strong), mode of inheritance: AR
• Omenn syndrome (Supportive), mode of inheritance: AR
• severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (Supportive), mode of inheritance: AR
• severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (Strong), mode of inheritance: AR
• recombinase activating gene 2 deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Severe combined immunodeficienc, autosomal recessive, T cell-negative (T-), B cell-negative (B-), natural killer cell-positive (NK+); Omenn syndrome; Combined cellular and humoral immune defects with granulomas	AR	Allergy/Immunology/Infectious	Antiinfectious prophylaxis (though special consideration is necessary related to the use of live vaccines) and early and aggressive treatment of infections may be beneficial; HSCT has been reported	Allergy/Immunology/Infectious; Dermatologic; Gastrointestinal	9630231; 10226883; 16276422; 20128425; 18463379; 21624848; 21184155; 21625022

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RAG2 gene.

• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas (21 variants)
• Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (21 variants)
• Combined immunodeficiency with skin granulomas (9 variants)
• Recombinase activating gene 2 deficiency (6 variants)
• Histiocytic medullary reticulosis (6 variants)
• not provided (3 variants)
• Severe combined immunodeficiency, B cell-negative (2 variants)
• Common variable immunodeficiency (2 variants)
• Recombinase activating gene 2 deficiency;Inborn error of immunity;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (1 variants)
• Combined immunodeficiency with skin granulomas;Recombinase activating gene 2 deficiency;Inborn error of immunity (1 variants)
• Histiocytic medullary reticulosis;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Recombinase activating gene 2 deficiency;Inborn error of immunity (1 variants)
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas;Histiocytic medullary reticulosis (1 variants)
• Severe combined immunodeficiency disease (1 variants)
• Inborn error of immunity;Recombinase activating gene 2 deficiency;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Histiocytic medullary reticulosis (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RAG2 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				175	1	176
missense	13	43	160	5	4	225
nonsense	6	9	1			16
start loss	1	1	1			3
frameshift	26	16	1			43
inframe indel			2			2
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			9	3	6	18
Total	46	69	174	183	11

Highest pathogenic variant AF is 0.0000395

Variants in RAG2

This is a list of pathogenic ClinVar variants found in the RAG2 region.

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

Position	Type	Phenotype	Significance	ClinVar
11-36575579-C-T		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive • Combined immunodeficiency due to partial RAG1 deficiency;Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Histiocytic medullary reticulosis • Combined immunodeficiency due to partial RAG1 deficiency	Likely pathogenic (Nov 11, 2023)
11-36575580-G-A		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas	Uncertain significance (Oct 24, 2022)
11-36575590-C-G		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Likely benign (Jun 28, 2023)
11-36575595-G-A		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive • Recombinase activating gene 1 deficiency	Uncertain significance (Feb 26, 2024)
11-36575597-T-A		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Uncertain significance (Jul 24, 2022)
11-36575610-A-G		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Uncertain significance (Jan 22, 2024)
11-36575611-T-C		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Likely benign (Oct 12, 2023)
11-36575614-G-C		Inborn genetic diseases	Uncertain significance (Aug 13, 2021)
11-36575617-T-C		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Likely benign (Jul 21, 2023)
11-36575624-G-T		Severe combined immunodeficiency, B cell-negative • Combined immunodeficiency due to partial RAG1 deficiency • Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas	Pathogenic/Likely pathogenic (Sep 27, 2023)
11-36575629-G-A		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas	Likely benign (Nov 01, 2023)
11-36575630-C-A		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Likely benign (Nov 06, 2023)
11-36575630-C-T		Severe combined immunodeficiency, B cell-negative • Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas • Combined immunodeficiency due to partial RAG1 deficiency • Severe combined immunodeficiency disease	Pathogenic (May 30, 2024)
11-36575631-G-A		not specified • Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive • Combined immunodeficiency due to partial RAG1 deficiency • RAG1-related disorder	Conflicting classifications of pathogenicity (Sep 15, 2023)
11-36575636-C-A		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Likely benign (May 05, 2023)
11-36575636-C-T		Combined immunodeficiency with skin granulomas • Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas	Pathogenic (Jun 20, 2023)
11-36575637-G-A		Combined immunodeficiency with skin granulomas • Combined immunodeficiency due to partial RAG1 deficiency • Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas • Severe combined immunodeficiency disease	Pathogenic (Feb 17, 2024)
11-36575647-G-A		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Likely benign (Dec 23, 2022)
11-36575647-G-T		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas	Uncertain significance (Apr 03, 2021)
11-36575649-T-A		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas • Combined immunodeficiency due to partial RAG1 deficiency • Severe combined immunodeficiency disease	Likely pathogenic (Jun 14, 2024)
11-36575652-C-G		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas • Combined immunodeficiency due to partial RAG1 deficiency;Histiocytic medullary reticulosis;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas • Combined immunodeficiency due to partial RAG1 deficiency	Pathogenic/Likely pathogenic (Mar 25, 2024)
11-36575680-T-A		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Likely benign (Jun 26, 2019)
11-36575695-C-T		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Likely benign (Jul 03, 2023)
11-36575697-A-G		Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Likely pathogenic (Feb 28, 2020)
11-36575700-G-A		Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Uncertain significance (Feb 15, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RAG2	protein_coding	protein_coding	ENST00000311485	1	22706

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0203	0.964	125709	0	38	125747	0.000151

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.197	257	266	0.966	0.0000132	3504
Missense in Polyphen		134	152.08	0.8811		2054
Synonymous	0.234	90	92.9	0.969	0.00000424	1007
Loss of Function	2.10	5	13.3	0.377	6.71e-7	201

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000296	0.000296
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000193	0.000193
Middle Eastern	0.0000544	0.0000544
South Asian	0.000131	0.000131
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Core component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination. V(D)J recombination assembles a diverse repertoire of immunoglobulin and T-cell receptor genes in developing B and T- lymphocytes through rearrangement of different V (variable), in some cases D (diversity), and J (joining) gene segments. DNA cleavage by the RAG complex occurs in 2 steps: a first nick is introduced in the top strand immediately upstream of the heptamer, generating a 3'-hydroxyl group that can attack the phosphodiester bond on the opposite strand in a direct transesterification reaction, thereby creating 4 DNA ends: 2 hairpin coding ends and 2 blunt, 5'-phosphorylated ends. The chromatin structure plays an essential role in the V(D)J recombination reactions and the presence of histone H3 trimethylated at 'Lys-4' (H3K4me3) stimulates both the nicking and haipinning steps. The RAG complex also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B- cell antigen receptor (BCR) expressed on individual B-lymphocytes. The introduction of DNA breaks by the RAG complex on one immunoglobulin allele induces ATM-dependent repositioning of the other allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. In the RAG complex, RAG2 is not the catalytic component but is required for all known catalytic activities mediated by RAG1. It probably acts as a sensor of chromatin state that recruits the RAG complex to H3K4me3 (By similarity). {ECO:0000250}.
• Disease: DISEASE: Combined cellular and humoral immune defects with granulomas (CHIDG) [MIM:233650]: Immunodeficiency disease with granulomas in the skin, mucous membranes, and internal organs. Other characteristics include hypogammaglobulinemia, a diminished number of T and B-cells, and sparse thymic tissue on ultrasonography. {ECO:0000269|PubMed:18463379}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Severe combined immunodeficiency autosomal recessive T- cell-negative/B-cell-negative/NK-cell-positive (T(-)B(-)NK(+) SCID) [MIM:601457]: A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. {ECO:0000269|PubMed:8810255}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Omenn syndrome (OS) [MIM:603554]: Severe immunodeficiency characterized by the presence of activated, anergic, oligoclonal T-cells, hypereosinophilia, and high IgE levels. {ECO:0000269|PubMed:9630231}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Primary immunodeficiency - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);MAPK6-MAPK4 signaling;Signal Transduction;MAPK6/MAPK4 signaling;MAPK family signaling cascades;C-MYB transcription factor network (Consensus)

Recessive Scores

• pRec: 0.607

Intolerance Scores

• loftool: 0.206
• rvis_EVS: 0.02
• rvis_percentile_EVS: 55.61

Haploinsufficiency Scores

• pHI: 0.0858
• hipred: N
• hipred_score: 0.444
• ghis: 0.405

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.935

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Rag2
• Phenotype: hematopoietic system 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); reproductive system phenotype; normal 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; liver/biliary system phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; skeleton phenotype; digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); 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); endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: rag2
• Affected structure: lymphocyte
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: B cell lineage commitment;pre-B cell allelic exclusion;B cell homeostatic proliferation;T cell lineage commitment;chromatin organization;protein ubiquitination;B cell differentiation;T cell differentiation in thymus;V(D)J recombination;defense response to bacterium;positive regulation of organ growth
• Cellular component: nucleoplasm;DNA recombinase complex
• Molecular function: DNA binding;chromatin binding;phosphatidylinositol-4,5-bisphosphate binding;phosphatidylinositol-3,4,5-trisphosphate binding;zinc ion binding;methylated histone binding;phosphatidylinositol binding;phosphatidylinositol-3,4-bisphosphate binding;sequence-specific DNA binding;ubiquitin protein ligase activity;phosphatidylinositol-3,5-bisphosphate binding