Combined immunodeficiency with skin granulomas: genes and variants

Genes linked to Combined immunodeficiency with skin granulomas

• 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.

  49 disease-causing and 249 uncertain variants in RAG1 are linked to Combined immunodeficiency with skin granulomas.

• 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.

  33 disease-causing and 142 uncertain variants in RAG2 are linked to Combined immunodeficiency with skin granulomas.

Where Combined immunodeficiency with skin granulomas variants cluster

• RAG1 NBD (positions 392–459): 9 of 49 disease-causing changes, 2.8× more than its size predicts.
• RAG2 PHD-type (positions 416–484): 8 of 33 disease-causing changes, 1.9× more than its size predicts.

Known disease-causing variants in Combined immunodeficiency with skin granulomas

Showing 60 of 82.

Uncertain variants in Combined immunodeficiency with skin granulomas that look disease-causing

Which prediction tools work for Combined immunodeficiency with skin granulomas

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

• MetaLR: 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)
• REVEL: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 98 out of 100
• CADD: 95 out of 100
• PolyPhen-2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 88 out of 100

Same protein, different disease

• Recombinase activating gene 1 deficiency is also caused by RAG1 variants; they fall in the same places as the Combined immunodeficiency with skin granulomas variants (8 disease-causing).
• Recombinase activating gene 2 deficiency is also caused by RAG2 variants; they fall partly in the same places as the Combined immunodeficiency with skin granulomas variants (25 disease-causing).
• Histiocytic medullary reticulosis is also caused by RAG2 variants; they fall partly in the same places as the Combined immunodeficiency with skin granulomas variants (14 disease-causing).
• Inborn error of immunity is also caused by RAG2 variants; they fall partly in the same places as the Combined immunodeficiency with skin granulomas variants (10 disease-causing).

Diseases related to Combined immunodeficiency with skin granulomas

• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, also linked to RAG1 and RAG2
• Severe combined immunodeficiency disease, also linked to RAG1 and RAG2
• Histiocytic medullary reticulosis, also linked to RAG1 and RAG2
• Recombinase activating gene 2 deficiency, also linked to RAG2
• 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
• Recombinase activating gene 1 deficiency, also linked to RAG1
• Common variable immunodeficiency, also linked to RAG2

Frequently asked questions

Which genes are linked to Combined immunodeficiency with skin granulomas?

In CATVariant, Combined immunodeficiency with skin granulomas is linked to 2 analyzed proteins: RAG1 (V(D)J recombination-activating protein 1) and RAG2 (V(D)J recombination-activating protein 2).

How many genetic variants are linked to Combined immunodeficiency with skin granulomas?

556 variants: 82 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 391 are of uncertain significance or have conflicting reports.

Which uncertain variants in Combined immunodeficiency with skin granulomas look disease-causing?

3 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example RAG2 M459V, RAG1 G709A and RAG2 L155H. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Combined immunodeficiency with skin granulomas?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.98, based on 80 disease-causing and 27 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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