CARD11

Chr 7

caspase recruitment domain family member 11

Also known as: BENTA, BIMP3, CARMA1, IMD11, IMD11A, PPBL

NCBI Gene: 84433 ENSG00000198286 UniProt: Q9BXL7

CARD11 encodes an adapter protein that transduces NF-kappa-B activation downstream of T-cell and B-cell receptor signaling by forming multiprotein complexes with BCL10 and MALT1. Mutations cause primary immunodeficiencies including B-cell expansion with NF-kappa-B activation and T-cell anergy, immunodeficiency with atopic dermatitis, and severe combined immunodeficiency, affecting adaptive immune responses. Inheritance can be either autosomal dominant or autosomal recessive depending on the specific variant.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the membrane-associated guanylate kinase (MAGUK) family, a class of proteins that functions as molecular scaffolds for the assembly of multiprotein complexes at specialized regions of the plasma membrane. This protein is also a member of the CARD protein family, which is defined by carrying a characteristic caspase-associated recruitment domain (CARD). This protein has a domain structure similar to that of CARD14 protein. The CARD domains of both proteins have been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. When expressed in cells, this protein activated NF-kappaB and induced the phosphorylation of BCL10. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.23

Clinical Summary— CARD11

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Gene-Disease Validity (ClinGen)

BENTA disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.23LOEUF

pLI 1.000

Z-score 6.45

OE 0.13 (0.07–0.23)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.54Z-score

OE missense 0.64 (0.59–0.69)

481 obs / 755.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.13 (0.07–0.23)

0≤0.351.4

Missense OE?0.64 (0.59–0.69)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 8 / 63.5Missense obs/exp: 481 / 755.0Syn Z: -1.32

This gene — mechanism propensity

0.4389th %ile

GOF

0.4875th %ile

LOF

0.63top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.23

GOF1 literature citation

DN1 literature citation

Literature Evidence

DNIn contrast, patients carrying loss-of-function (LOF), dominant negative (DN) CARD11 mutations present with severe atopic disease.1

GOFGermline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor ÃÂºB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (los2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References