Table 2. Variants Identified in Patients with Familial Intracranial Aneurysms according to the Application of Filtering Strategy and Segregation.
| Gene | Transcript ID | c. notation p. notation |
rs ID | MAF | Pathogenicity Predictions† | ACMG Interpretation‡ | Subjects | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| gnomAD/ KRGDB | SIFT | Polyphen2 | GERP | CADD | REVEL | M-CAP | pLI | %HI | Classification | Fm | Member* | ||||
| PLOD3 | NM_001084.4 | c.1315G>A p.Ala439Thr |
rs138610113 | 0.000403/ 0.002105 | 0.011 | 0.646 | 5.13 | 21.9 | 0.087 | 0.06 | 0.06 | 0.65 | VUS PM1 + PP3 |
A | II-2*, III-1*, III-2* |
| NTM | NM_001048209.1 | c.968C>T p.Thr323Met |
rs755518659 | 0.000018/ 0.000000 | 0.223 | 0.958 | 5.21 | 23.6 | 0.247 | 0.138 | 1 | 14.03 | VUS PM2 +PP3 |
B | II-1, II-2*, II-4* |
| RYR2 | NM_001035.2 | c.3595G>A p.Asp1199Asn |
rs752376759 | 0.000065/ 0.000000 | 0.153 | 0.733 | 0.235 | 8.116 | 0.028 | 0.003 | 0 | 80.67 | LPV PM1 + PM2 + PP2 + PP3 |
B | II-2*, II-3, II-4* |
| PCNT | NM_006031.5 | c.545G>A p.Arg182His |
rs193268784 | 0.000113/ 0.003143 | 0.001 | 1 | 5.62 | 32 | 0.22 | 0.037 | 0.04 | 23.92 | LBV PM2 + BP1 + BP4 |
B | II-2*, II-3, II-4* |
| NSMCE2 | NM_173685.2 | c.217C>T p.Arg73Trp |
rs201903722 | 0.000191/ 0.007079 | 0.241 | 0.001 | 1.25 | 13.01 | 0.493 | 0.241 | 0 | 52.28 | VUS PM2 + PP3 + BP1 |
B | II-1, II-2*, II-3, II-4* |
| GBA | NM_000157.3 | c.680A>G p.Asn227Ser |
rs364897 | 0.000074/ 0.000262 | 0.001 | 0.979 | 4.3 | 23.6 | 0.244 | N/A | 0 | 51.13 | LPV PS3 + PM1 + PM2 + PP5 |
B | II-1, II-2*, II-3, II-4* |
| CHST14 | NM_130468.3 | c.58C>T p.Arg20Trp |
rs577809616 | 0.000216/ 0.003584 | 0 | 0.998 | 3.8 | 27.9 | 0.37 | 0.771 | 0.45 | 35.81 | VUS PM2 + PP2 + PP3 |
C | II-2*, II-4* |
| SLC2A10 | NM_030777.3 | c.931G>A p.Val311Ile |
rs139932041 | 0.000287/ 0.000786 | 0.283 | 0.084 | 3.88 | 14.58 | 0.14 | 0.018 | 0 | 71.81 | VUS PM1 + PM2 |
C | II-2*, II-4* |
| ADAMTS2 | NM_014244.4 | c.268G>A p.Ala90Thr |
rs776393146 | 0.000095/ 0.005500 | 0.595 | 0.212 | 4.18 | 19.61 | 0.044 | 0.008 | 0.97 | 25.76 | VUS PM1 + PM2 + BP1 |
C | II-2*, II-3, II-4* |
| NOTCH1 | NM_017617.4 | c.5422G>A p.Asp1808Asn |
rs571739078 | 0.000043/ 0.000786 | 0.091 | 0.676 | 4.55 | 23.7 | 0.381 | 0.512 | 1 | 0.15 | VUS PM2 + PP2 + PP3 |
C | II-2*, II-3, II-4* |
| C9orf92 | NM_001271829.1 | c.106C>T p.Gln36Ter | N/A | 0.000000/ 0.000000 | N/A | N/A | 1.98 | N/A | N/A | N/A | 0 | 0.52 | VUS PM2 |
C | II-2*, II-3, II-4* |
*IA-affected subject, †Pathogenicity thresholds: SIFT (≤ 0.05), Polyphen2 (≥ 0.9), GERP (≥ 2), CADD (≥ 20), REVEL (≥ 0.5), M-CAP (≥ 0.025), pLI (≥ 0.9), and %HI (≤ 10%), ‡ACMG standards and guidelines: VUS, LBV, LPV, each pathogenic criterion is weighted as very strong (PVS1), strong (PS1–4); moderate (PM1–6), or supporting (PP1–5), and each benign criterion is weighted as stand-alone (BA1), strong (BS1– 4), or supporting (BP1–6). ACMG = American College of Medical Genetics and Genomics, CADD = Combined Annotation Dependent Depletion, c.notation = nucleotide change, Fm = family, GERP = Genomic Evolutionary Rate Profiling, HI = haploinsufficient, KRGDB = Korean reference genome database, LBV = likely benign variant, LPV = likely pathogenic variant, MAF = minor allele frequency, M-CAP = Mendelian Clinically Applicable Pathogenicity, N/A = not available, pLI = the probability of being loss-of-function intolerant, p.notation = amino acid change, REVEL = rare exome variant ensemble learner, rs = reference, SIFT = Sorting Intolerant From Tolerant, SNP = single nucleotide polymorphism, VUS = variant of uncertain significance