Prediction of Gain-of-Function and Loss-of-Function Mutations Using Combined Annotation Dependent Depletion

The study utilized Combined Annotation Dependent Depletion (CADD) to predict gain-of-function (GOF) and loss-of-function (LOF) mutations by analyzing C-scores, which integrate multiple annotations. The research found distinct mean C-scores for GOF (27.28) and LOF (36.38) variants, indicating a significant difference (p<0.05) between the two groups. A cut-off C-score of 25 for GOF and 35 for LOF was established, accurately predicting approximately 72% of GOF and 75% of LOF variants. The study highlighted that nonsense mutations, which constituted over 75% of the dataset, had higher mean C-scores due to their significant physicochemical changes. These findings suggested that C-scores could serve as indicators for mutation classification, with further evidence needed for pathogenicity assessment.