Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive: genes and variants

Genes linked to Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive

• RAG1: V(D)J recombination-activating protein 1

  It initiates V(D)J recombination by cutting antigen-receptor gene segments, creating the enormous receptor diversity required for adaptive immunity. Biallelic severe loss-of-function variants cause severe combined immunodeficiency, while hypomorphic alleles can cause Omenn syndrome or combined immunodeficiency with autoimmunity.

  52 disease-causing and 263 uncertain variants in RAG1 are linked to Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive.

• RAG2: V(D)J recombination-activating protein 2

  Together with RAG1, it restricts and activates V(D)J recombination during lymphocyte development so immunoglobulin and T-cell receptor genes can be assembled. Biallelic loss-of-function variants cause severe combined immunodeficiency or hypomorphic immune-dysregulation syndromes.

  32 disease-causing and 148 uncertain variants in RAG2 are linked to Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive.

• JAK3: Tyrosine-protein kinase JAK3

  It carries signals from cytokine receptors using the common gamma chain and is essential for T-cell and NK-cell development. Biallelic loss-of-function variants cause severe combined immunodeficiency, while activating somatic variants occur in selected leukemias and lymphomas.

  0 disease-causing and 1 uncertain variants in JAK3 are linked to Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive.

Weakly linked (only a few uncertain records): ADA.

Where Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive variants cluster

• RAG1 NBD (positions 392–459): 10 of 52 disease-causing changes, 3.0× more than its size predicts.
• RAG2 PHD-type (positions 416–484): 8 of 32 disease-causing changes, 1.9× more than its size predicts.

Known disease-causing variants in Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive

Showing 60 of 84.

Uncertain variants in Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive that look disease-causing

Which prediction tools work for Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• SIFT: 99 out of 100
• REVEL: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 97 out of 100
• PolyPhen-2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 89 out of 100

Same protein, different disease

• Combined immunodeficiency due to partial RAG1 deficiency is also caused by RAG1 variants; they fall mostly in different places as the Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive variants (13 disease-causing).
• Histiocytic medullary reticulosis is also caused by RAG1 variants; they fall mostly in different places as the Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive variants (11 disease-causing).
• Recombinase activating gene 1 deficiency is also caused by RAG1 variants; they fall in the same places as the Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive variants (8 disease-causing).
• Recombinase activating gene 2 deficiency is also caused by RAG2 variants; they fall partly in the same places as the Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive variants (25 disease-causing).
• Histiocytic medullary reticulosis is also caused by RAG2 variants; they fall partly in the same places as the Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive variants (14 disease-causing).
• Inborn error of immunity is also caused by RAG2 variants; they fall partly in the same places as the Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive variants (10 disease-causing).
• Severe combined immunodeficiency disease is also caused by RAG2 variants; they fall partly in the same places as the Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive variants (7 disease-causing).

Diseases related to Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive

• Severe combined immunodeficiency disease, also linked to JAK3, RAG1 and RAG2
• Combined immunodeficiency with skin granulomas, also linked to RAG1 and RAG2
• Histiocytic medullary reticulosis, also linked to RAG1 and RAG2
• Recombinase activating gene 2 deficiency, also linked to RAG2
• T-B+ severe combined immunodeficiency due to JAK3 deficiency, also linked to JAK3
• Inherited Immunodeficiency Diseases, also linked to RAG1
• Combined immunodeficiency due to partial RAG1 deficiency, also linked to RAG1
• Inborn error of immunity, also linked to RAG2
• Essential thrombocythemia, also linked to JAK3
• Recombinase activating gene 1 deficiency, also linked to RAG1
• Common variable immunodeficiency, also linked to RAG2
• Acquired polycythemia vera, also linked to JAK3

Frequently asked questions

Which genes are linked to Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive?

In CATVariant, Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive is linked to 3 analyzed proteins: RAG1 (V(D)J recombination-activating protein 1), RAG2 (V(D)J recombination-activating protein 2) and JAK3 (Tyrosine-protein kinase JAK3).

How many genetic variants are linked to Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive?

580 variants: 84 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 412 are of uncertain significance or have conflicting reports.

Which uncertain variants in Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive look disease-causing?

2 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example RAG2 M459V and RAG2 L155H. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.99, based on 82 disease-causing and 57 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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