Research ArticleGENETIC DISEASE

Predicting functional effects of missense variants in voltage-gated sodium and calcium channels

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Science Translational Medicine  12 Aug 2020:
Vol. 12, Issue 556, eaay6848
DOI: 10.1126/scitranslmed.aay6848

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Predicting ion channel variant phenotypes

Ion channel variants have been associated with disease, predominantly neurological. Heyne et al. developed a tool to predict the functional effects of variants in disease-associated voltage-gated sodium and calcium ion channels using machine learning–based statistical models. Loss of function versus gain of function (LOF or GOF) was predicted separately from neutrality versus pathogenicity. Their model was trained to classify variant effects using protein sequences and structures containing missense variants with known or highly probable effects and validated against experimentally tested variants and in cohorts including individuals with epilepsy and autism. This work could have implications for ion channel and clinical genetics research.

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