Table 2.
Predicted protein structure and disease-causing effects of mutations in AC family.
| Gene | Exon | Variation | Polyphen-2 [sensitivity–specificity] b | Mutation taster c | I-Mutant3.0 (kcal/mol) d | SIFT e | EXAC f | Overall evaluated pathogenicity | |||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Nucleotide a | Protein a | Type | Status | ||||||||
| ADCY1 | 22 | c.2818 G>A | p.Ala940Thr | Missense | Homo | B (0.005) [0.97–0.740] | B (1.00) | DS (−0.45) | T (0.05) | Novel | Benign |
| 22 | c. 3090G>A | p.Val984Met | Synonymous | Homo | PD (1.000) [0.00–1.00] | B (1.00) | DS (−1.37) | NT (0.05) | Novel | Benign | |
| 22 | c. 3184G>A | p.Gly1062Ser | Missense | Homo | PD (1.000) [0.00–1.00] | B (1.00) | DS (−1.37) | T (1.00) | Novel | Benign | |
| ADCY6 | 23 | c. 1640T>C | p.Ile547Thr | Missense | Hetro | PD (1.000) [0.00–1.00] | B (0.60) | DS (−2.22) | NT (0.05) | Novel | Benign |
| 23 | c. 2029C>A | p.Leu677Met | Missense | Homo | PD (0.716) [0.86–0.92] | B (0.60) | DS −1.08) | T (0.05) | Novel | Benign | |
| 23 | c. 3007G>A | p.Glu1003Lys | Missense | Homo | PD (0.989) [0.72–0.97] | De (0.60) | DS (−0.63) | NT (1.00) | Pathogenic | Pathogenic | |
| 23 | c. 3346C>T | p.Arg1116Cys | Missense | Homo | PD (1.000) [0.00–1.00] | De (0.00) | DS (−1.21) | NT (1.00) | Pathogenic | Pathogenic | |
| 23 | c. 2975A>G | p.Tyr992Cys | Missense | Hetro | PD (1.000) [0.00–1.00] | De (0.60) | DS (−0.89) | NT (0.05) | Pathogenic | Likely pathogenic | |
c, variation at cDNA level; G, guvanin; G, guanine; A, adenine; T, thymine C, cytosine; p, variation at protein level; Ala, alanine; Thr, tyrosine; Val, valine; Met, methionine; Gly, glycine; Ser, serine; Ile, isoleucine; Leu, leucine; Glu, glutamic acid; Lys, lysine; Arg, arginine; Cys, cysteine; Tyr, tyrosine; Homo, homozygote; Hetro; heterozygous; B, benign; PD, probably damaging; DC, disease-causing; De, deleterious; DS, decrease stability; NT, not tolerated; T, tolerated.
All nucleotide and amino acids are abbreviated according to the International Union of Pure and Applied Chemistry (IUPAC).
Polymorphism phenotyping v2 (Polyphen-2) is used to predict the possible impact of amino acid substitutions on the stability and function of proteins using structural and comparative evolutionary considerations.
Mutation taster is applied to evaluate the disease-causing potential of sequence alterations.
I-Mutant3.0 support vector machine (SVM)-based tools were used for the automatic prediction of protein stability changes upon single-point mutations
Sorting intolerant from tolerant (SIFT) program is used to predict whether an amino acid substitution affects protein function so that users can prioritize substitutions for further study.
ExAC databases were used to identify individuals expected to exhibit a childhood disorder based on concordance with disease inheritance modes: heterozygous (for dominant), homozygous (for recessive), or hemizygous (for X-linked recessive conditions).