TABLE 2.
Genetic characteristic and ACMG scoring of the CACNA1A mutations.
| Case no. | Mutation | Inheritance | MAF | MAF-EAS | SIFTa | PP2_Vara | MutationTastera | M_CAPa | DDG (kcal/mol) | ACMG scoring | ACMG pathogenicity |
| Case 1 | p.Gly989Argfs*78 | De novo | – | – | – | – | – | – | – | PVS1 + PS2 + PM2 | Pathogenic |
| Case 2 | c.3089 + 1G > A | De novo | – | – | – | – | – | – | – | PVS1 + PS2 + PM2 | Pathogenic |
| Case 3 | c.4755 + 1G > T | De novo | – | – | – | – | – | – | – | PVS1 + PS2 + PM2 | Pathogenic |
| Case 4 | c.6340-1G > A | De novo | – | – | – | – | – | – | – | PVS1 + PS2 + PM2 | Pathogenic |
| Case 5 | p.Arg68Leu | De novo | – | – | 0.002 (D) | 0.319 (B) | 0.999 (D) | 0.753 (D) | –0.73 | PS2 + PM2 + PP3 | Likely pathogenic |
| Case 6 | p.Gly1322Glu | De novo | – | – | 0.011 (D) | 1 (D) | 1 (D) | 0.687 (D) | –1.47 | PS2 + PM2 + PP3 | Likely pathogenic |
| Case 7 | p.Arg1678Cys | De novo | – | – | 0 (D) | 1 (D) | 1 (D) | 0.833 (D) | –0.89 | PS2 + PM2 + PP3 | Likely pathogenic |
| Case 8 | p.Ser1798Leu | De novo | – | – | 0 (D) | 0.998 (D) | 1 (D) | 0.794 (D) | –0.15 | PS2 + PM2 + PP3 | Likely pathogenic |
| Case 9 | p.Ser1078Leu p.Glu2021Lys |
Paternal Maternal |
1.4 × 10–5 3.7 × 10–4 |
2.1 × 10–4 4.8 × 10–3 |
0.09 (T) 0.072 (T) |
0.057 (B) 0.441 (B) |
1 (P) 1 (D) | 0.619 (D) 0.25 (D) |
0.44 0.28 | PM2 + PP3 PM2 + PP3 | Uncertain significance |
| Case 10 | p.Pro1993Leu p.Ile1631Val |
Paternal Maternal |
6.1 × 10–6 1.3 × 10–4 |
– 1.9 × 10–3 | 0.304 (T) 0.58 (T) |
0.738 (D) 0.262 (B) |
1 (D) 0.997 (D) | 0.221 (D) 0.076 (D) |
0.19 –1.17 | PM2 + PP3 PM2 + PP3 | Uncertain significance |
ACMG, American College of Medical Genetics and Genomics; B, benign; D, damaging; DDG, protein stability indicated by free energy change value; MAF, minor allele frequency from gnomAD; MAF-EAS, minor allele frequency from gnomAD-East Asian population; M_CAP, Mendelian Clinically Applicable Pathogenicity; P, polymorphism; PM2, absent in population databases; PP2_Var, Polyphen2_HVAR; PP3, multiple lines of computational evidence support a deleterious effect on the gene/gene product; PS2, De novo (paternity and maternity confirmed); PVS1, predicted null variant in a gene where loss of function (LOF) is a known mechanism of disease; SIFT, Sorting Intolerant From Tolerant; T, tolerable.
aTypical results of damage effect prediction of the CACNA1A mutations in this table were selected from 23 algorithms in silico missense prediction (http://varcards.biols.ac.cn/).
*means a premature termination of the protein caused by a frameshift mutation.