Table 2.
Pathogenicity chart of the mutations identified in Pakistani families.
| (a) | ||||||||||
| ID | Gene | Transcript ID | Exon | cDNA Change | Protein Change | ACMG Interpretation |
gnomAD
Frequency |
CADD-
Score |
Mutation
Taster |
Polyphen-2 |
| Fam. 1 | ASPM | NM_018136.4 | 23 | c.9601C>T | p.(Gln3201*) | Pathogenic (PVS1, PM2, PP3) |
- | 41 | Disease causing (6.0) | NA |
| WDR62 | NM_001083961.1 | 27 | c.3316A>G | p.(Ser1106Gly) | Uncertain significance (PM2) |
0.0000325 | 19.21 | Polymorphism (56) | Benign (0.09) | |
| Fam. 2 | ASPM | NM_018136.4 | 3 | c.719_720delCT | p.(Ser240Cysfs*16) | NA | 0.0000325 | - | Disease causing | NA |
| CEP63 | NM_025180.3 | 12 | c.1261A>T | p.(Thr421Ser) | Uncertain significance (PM2, BP1) |
- | 25.1 | Disease causing (58) | Probably damaging (1.000) | |
| Fam. 3 | ASPM | NM_018136.4 | 23 | c.9492T>G | p.(Tyr3164*) | Pathogenic (PVS1, PM2, PP5) |
- | 35 | Disease causing (6.0) | NA |
| RAD50 | NM_005732.3 | 24 | c.3643C>G | p.(Leu1215Val) | Likely benign (PM1, PM2, BP1, BP4) |
- | 23.5 | Disease causing (32) | Probably damaging (1.000) | |
| Fam. 4 | CENPJ | NM_018451.4 | 14 | c.3586G>A (c.3541_3618del) † |
p.(Asp1196Asn) p.(Val1181_Val1206del) †† |
Likely pathogenic (PM1, PM2, PP3, PP5) |
- | 28.1 | Disease Causing (23) | Probably Damaging (1.000) |
| PCNT | NM_006031.5 | 28 | c.5767C>T | p.(Arg1923*) | Pathogenic (PVS1, PM2, PP3, PP5) |
0.0000122 | 42 | Disease Causing (6.0) | NA | |
| Fam. 5 | CENPJ | NM_018451.4 | 14 | c.3586G>A (c.3541_3618del) † |
p.(Asp1196Asn) p.(Val1181_Val1206del) †† |
Likely pathogenic (PM1, PM2, PP3, PP5) |
- | 28.1 | Disease Causing (23) | Probably Damaging (1.000) |
| (b) | ||||||||||
| ID | Gene | Provean | PANTHER | PhD-SNP | SIFT | SNAP | Meta SNP | MuPro | SNPs&GO | MetaDome |
| Fam. 1 | ASPM | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| WDR62 | Neutral (−1.216) |
NA | Disease causing (0.589) |
Disease causing (0.010) |
Disease causing (0.505) |
Disease causing (0.514) |
DDG = −1.6848846 (DECREASE stability) |
Neutral | Slightly tolerant (0.93) |
|
| Fam. 2 | ASPM | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| CEP63 | Deleterious (−2.830) |
NA | Neutral (0.380) |
NA | NA | Neutral (0.203) |
DDG = −0.54948253 (DECREASE stability) |
Neutral | Tolerant (1.33) |
|
| Fam. 3 | ASPM | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| RAD50 | Neutral (−2.238) |
Disease causing (0.603) |
Disease causing (0.591) |
Disease causing (0.010) |
Disease causing (0.645) |
Disease causing (0.654) |
DDG = −0.79919509 (DECREASE stability) |
Neutral | Intolerant (0.42) |
|
| Fam. 4 | CENPJ | Deleterious (−4.841) |
NA | Disease causing (0.833) |
Disease causing (0.000) |
Disease causing (0.685) |
Disease causing (0.706) |
DDG = −0.82129284 (DECREASE stability) |
Neutral | Intolerant (0.33) |
| PCNT | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| Fam. 5 | CENPJ | Deleterious (−4.841) |
NA | Disease causing (0.833) |
Disease causing (0.000) |
Disease causing (0.685) |
Disease causing (0.706) |
DDG = −0.82129284 (DECREASE stability) |
Neutral | Intolerant (0.33) |
Note: (a) † This particular cDNA mutation (78 bp deletion) resulted due to aberrant splicing examined by RT-PCT. †† Protein mutation due to a 78 bp in-frame deletion. Allele frequency shown in the column of gnomAD was based on two heterozygous alleles in WDR62, one allele of ASPM and two heterozygous alleles of PCNT. Numbers shown in brackets below the prediction statuses indicate the pathogenicity scores suggested by each tool. Mutations of ASPM and CENPJ are in homozygous forms whereas WDR62, CEP63, RAD50 and PCNT are in heterozygous states. Value reported under each prediction: PANTHER, PhD-SNP, SNAP and Meta-SNAP (scale is 0 to 1 and more than 0.5 score signifies disease causing); SIFT (positive values: more than 0.5 score shows neutral effects of mutation); and MuPro (a score less than 0 means the mutation decreases the protein stability. NA means data not available. (b) † This particular cDNA mutation (78 bp deletion) resulted due to aberrant splicing examined by RT-PCT. †† Protein mutation due to a 78 bp in-frame deletion. Mutations of ASPM and CENPJ are in homozygous forms whereas WDR62, CEP63, RAD50 and PCNT are in heterozygous states. Allele frequencies shown in the column of gnomAD were based on two heterozygous alleles in WDR62, one allele of ASPM and two heterozygous alleles of PCNT. Numbers shown in brackets below the prediction statuses indicate the pathogenicity scores suggested by each tool. Interpretation of values for PANTHER, PhD-SNP, SNAP and Meta-SNAP, scale is 0 to 1 and more than 0.5 score signifies disease causing; SIFT, positive values: more than 0.5 score shows neutral effects of mutation; and MuPro, a score less than 0 means the mutation decreases the protein stability. NA means data not available.