Table III.
Variants found in the 4 families presenting with CPN deficiency: Bioinformatic analysis
| Gene | Encoded protein | Protein function | OMIM | Variant | MAF (gnomAD) |
Prediction algorithms |
|||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| World | European | HSF 3.0 | SIFT | PolyPhen-2 | MutationTaster | ClinPred | |||||
| CPN1 | Carboxypeptidase N, subunit 1 | Kininase I | 603103 | c.533G>A p.(Gly178Asp) rs61751507 |
0.0034 | 0.0048 | Deleterious (0.02) | Probably damaging (0.996) | Polymorphism (1.37 × 10−7) | Damaging (0.997) | |
| c.582A>G p.(Glu194=) rs190183597 |
0.000058 | 0.000061 | Affects splicing | ||||||||
| c.734C>T p.(Thr245Met) rs3710700915 |
0.000032 | 0.0000309 | Deleterious (0.00) | Probably damaging (0.998) | Disease-causing (0.999) | Damaging (0.753) | |||||
| c.1299C>T p.(His433=) rs61733667 |
0.02721 | 0.03546 | |||||||||
| Associated variants | |||||||||||
| ACE | Angiotensin I–converting enzyme | Kininase II | 106180 | c.3053T>C p.(Ile1018Thr) rs4976 |
0.00115 | 0.000037 | Deleterious (0.00) | Probably damaging (0.999) | Disease-causing (0.999) | Tolerated (0.099) | |
| F12 | Factor XII, alias Hageman factor | KKS | 610618 | c.-4T>C rs1801020 common SNP |
0.6522 | 0.348030 | |||||
| HRH1 | Histamine H1 receptor | Endothelial H1 histamine receptor | 600167 | c.42G>A p.(Met14Ile) rs79314450 |
0.0014 | 0.00053 | Tolerated (0.058) | Possibly damaging (0.541) | Disease-causing (0.946) | Tolerated (0.024) | |
| KLKB1 | Plasma prekallikrein | KKS | 229000 | c.689T>A p.(Ile230Asn) rs142420360 |
0.000180 | 0.0003406 | Deleterious (0.00) | Probably damaging (0.999) | Disease-causing (0.992) | Tolerated (0.315) | |
| MASP2 | Mannan-binding lectin associated protease 2 | Complement convertase | 613791 | c.352C>T p.(Arg118Cys) rs147270785 |
0.00051 | 0.00064 | Deleterious (0.02) | Benign (0.143) | Disease-causing (0.999) | Tolerated (0.173) | |
| MPO | Myeloperoxidase | Neutrophil/mast cell granule enzyme | 606989 | c.752A>G p.(Met251Thr) rs56378716 |
0.01259 | 0.01317 | Deleterious (0.00) | Benign (0.032) | Disease-causing (0.999) | Tolerated (0.088) | |
| SERPINC1 | Antithrombin III | Control of coagulation, KKS, and plasmin | 107300 | c.749C>T p.(Thr250Ile) rs144084678 |
0.00003 | 0.00005 | Deleterious (0.00) | Probably damaging (0.993) | Disease-causing (1.00) | Damaging (0.841) | |
| SERPING1 | C1-INH | Control of KKS and complement | 606860 | c.1438G>A p.(Val480Met) rs4926 |
0.212 | 0.274 | Tolerated (0.084) | Benign (0.034) | Polymorphism (0.999) | Tolerated (0.037) | |
| XPNPEP2 | Membrane X-prolyl aminopeptidase (APP) | Membrane kininase | 300145 | c.-2399C>A rs3788853 |
0.2261 | 0.2233 | |||||
| c.644C>T rs138365897 |
0.00236 | 0.00349 | Deleterious (0.01) | Possibly damaging (0.871) | Disease-causing (0.995) | Tolerated (0.043) | |||||
The MAFs detected in the World and European populations are indicated according to gnomAD. The results from 4 prediction algorithms applied to missense substitutions are summarized: SIFT (with score), PolyPhen-2 (with probability score), and MutationTaster and ClinPred (with probability). The SIFT and PolyPhen-2 algorithms give scores ranging from 0 to 1. A mutation is predicted as “deleterious” by SIFT if its score is less than 0.05; otherwise it is predicted as “tolerated.” A mutation is predicted as “possibly damaging” by PolyPhen-2 if its score is greater than 0.15 and as “probably damaging” if it is greater than 0.85; otherwise it is predicted as “benign.” The MutationTaster algorithm indicates the probability of an alteration being a polymorphism or a disease-causing alteration. The scores range from 0 to 1, with a score of 1 indicating a high security of prediction. ClinPred incorporates machine-learning algorithms that use existing pathogenicity scores and benefits from normal population allele frequency. HSF 3.0 has been used as an algorithm for prediction of a synonymous variant.
gnomAD, Genome Aggregation Database v2.1.1; HSF 3.0, Human Splicing Finder system; MAF, minor allele frequency; OMIM, Online Mendelian Inheritance in Man; PolyPhen-2, Polymorphism Phenotyping v2; SIFT, Sorting Intolerant From Tolerant; SNP, single nucleotide polymorphism.