RAG2
recombination activating 2
Basic information
Region (hg38): 11:36575574-36598279
Links
Phenotypes
GenCC
Source:
- 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
- Omenn syndrome (Definitive), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Severe combined immunodeficienc, autosomal recessive, T cell-negative, B cell-negative, natural killer cell-positive; 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
- Combined immunodeficiency with skin granulomas;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (26 variants)
- Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas (15 variants)
- Combined immunodeficiency with skin granulomas (10 variants)
- Recombinase activating gene 2 deficiency (7 variants)
- Histiocytic medullary reticulosis (6 variants)
- not provided (5 variants)
- Severe combined immunodeficiency disease (3 variants)
- Severe combined immunodeficiency, B cell-negative (2 variants)
- Common variable immunodeficiency (2 variants)
- Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (2 variants)
- Histiocytic medullary reticulosis;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Combined immunodeficiency with skin granulomas (2 variants)
- Combined immunodeficiency with skin granulomas;Histiocytic medullary reticulosis;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (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)
- Atypical severe combined immunodeficiency due to complete RAG1/2 deficiency;Recombinase activating gene 2 deficiency;Inborn error of immunity (1 variants)
- Recombinase activating gene 2 deficiency;Inborn error of immunity;Histiocytic medullary reticulosis;Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (1 variants)
- Recombinase activating gene 2 deficiency;Inborn error of immunity;Combined immunodeficiency with skin granulomas (1 variants)
- Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;Histiocytic medullary reticulosis;Combined immunodeficiency with skin granulomas (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)
- Histiocytic medullary reticulosis;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)
- RAG2-related disorder (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. These statistics are base on transcript: . Only rare variants are included in the table.
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 | 174 | 175 | ||||
| missense | 14 | 41 | 173 | 237 | ||
| nonsense | 15 | 23 | ||||
| start loss | 1 | 2 | 3 | |||
| frameshift | 26 | 20 | 47 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 47 | 77 | 177 | 179 | 5 |
Highest pathogenic variant AF is 0.0000394638
Loading clinvar variants...
GnomAD
Source:
| 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:
- 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