Table 2.
Characteristics and Frequencies of CARD14 Coding Variants
| CARD14 Exon | cDNA Mutation and Corresponding Protein Change | Protein Domain | PolyPhen227-Predicted Effect on Protein Function | Effect on NF-kB Activation (FC versus Wild-Type CARD14sh) | Allele Frequency in Cases (Number Sampled) | Allele Frequency in Controls (Number Sampled) |
|---|---|---|---|---|---|---|
| 2 | c.112C>T (p.Arg38Cys) | CARD | probably damaging | 0.11 | 0.00019 (2,691) | 0 (1,271) |
| 2 | c.185G>A (p.Arg62Gln) (rs115582620) | CARD | benign | 1.06 | 0.0014 (3,284) | 0.00084 (1,797) |
| 3 | c.349G>A (p.Gly117Ser) | none | possibly damaging | 3.71 | 0.00023 (6,630) | 0 (4,731) |
| 3 | c.349+5G>A | none | NA | ND | 0 (2,871) | 0 (1,339) |
| 4 | c.413A>C (p.Glu138Ala) | coiled-coil | probably damaging | 8.95 | 0.00015 (3,488) | 0 (1,902) |
| 4 | c.424G>A (p.Glu142Lys) | coiled-coil | probably damaging | 4.03 | 0.00012 (4,107) | 0 (1,874) |
| 4 | c.425A>G (p.Glu142Gly) | coiled-coil | probably damaging | 5.00 | 0.00019 (2,848) | 0 (1,451) |
| 4 | c.449T>G (p.Leu150Arg) (rs146214639) | coiled-coil | probably damaging | 1.79 | 0.0025 (6,140) | 0.0016 (4,614) |
| 4 | c.511C>A (p.His171Asn) | coiled-coil | benign | 0.68 (5.95 with TNF-α stimulation) | 0.00025 (4,077) | 0 (1,858) |
| 4 | c.526G>C (p.Asp176His) (rs144475004) | coiled-coil | probably damaging | 2.78 | 0.00056 (3,575) | 0.00062 (1,609) |
| 4 | c.536G>A (p.Arg179His) | coiled-coil | probably damaging | 1.38 (2.19 with TNF-α stimulation) | 0.00025 (4,061) | 0.00027 (1,848) |
| 4 | c.571G>T (p.Val191Leu) | coiled-coil | benign | 1.02 | 0.00014 (3,575) | 0 (1,613) |
| 4 | c.599G>A (p.Ser200Asn) | coiled-coila | benign | 0.67 | 0.011 (6,163) | 0.0084 (4,624) |
| 6 | c.854A>G (p.Asp285Gly) | none | possibly damaging | 1.14 | 0.00019 (2,673) | 0 (1,467) |
| 13 | c.1778T>A (p.Ile593Asn) | PDZ | probably damaging | 1.30 | 0.00024 (2,049) | 0.00048 (1,039) |
| 15 | c.2044C>T (p.Arg682Trp) (rs117918077) | SH3 | probably damaging | 0.95 | 0.013 (2,169) | 0.012 (1,042) |
| 15 | c.2140G>A (p.Gly714Ser) (rs151150961) | SH3 | benign | 1.02 | 0.0021 (2,105) | 0.0014 (1,038) |
| 21 | c.2919C>G (p.Asp973Glu) (rs144285237) | GUK | benign | NDb | 0.0024 (5,177) | 0.0015 (4,099) |
CARD14 missense variants are listed with details on their locations in critical CARD14 protein domains, their predicted effect on protein function from PolyPhen2,27 their effect on NF-kB activation (fold change compared to unstimulated wild-type CARD14sh; see also Figure 3), and frequencies in unrelated cases and controls of European ancestry. The number of individuals screened is in parenthesis. The following abbreviations are used: FC, fold change; and ND, not done.
The p.Ser200 residue lies within a 6 bp sequence separating two predicted coiled-coil regions and thus could be considered part of an overarching coiled-coil domain. Also, variant rs114688446 was identified at this location in dbSNP, but the amino acid change (p.Ser200Ile) was different.
The impact of p.Asp973Glu on NF-kB activation could not be tested because it is exclusive to CARD14fl, for which a full-length cDNA clone was unavailable. Additional data on these variants are presented in Table S1.