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

Henrike O Heyne, David Baez-Nieto, Sumaiya Iqbal, Duncan S Palmer, Andreas Brunklaus, Patrick May, Katrine M Johannesen, Stephan Lauxmann, Johannes R Lemke, Rikke S Møller, Eduardo Pérez-Palma, Ute I Scholl, Steffen Syrbe, Holger Lerche, Dennis Lal, Arthur J Campbell, Hao-Ran Wang, Jen Pan, Mark J Daly, Epi25 Collaborative


Malfunctions of voltage-gated sodium and calcium channels (encoded by SCNxA and CACNA1x family genes, respectively) have been associated with severe neurologic, psychiatric, cardiac, and other diseases. Altered channel activity is frequently grouped into gain or loss of ion channel function (GOF or LOF, respectively) that often corresponds not only to clinical disease manifestations but also to differences in drug response. Experimental studies of channel function are therefore important, but laborious and usually focus only on a few variants at a time. On the basis of known gene-disease mechanisms of 19 different diseases, we inferred LOF (n = 518) and GOF (n = 309) likely pathogenic variants from the disease phenotypes of variant carriers. By training a machine learning model on sequence- and structure-based features, we predicted LOF or GOF effects [area under the receiver operating characteristics curve (ROC) = 0.85] of likely pathogenic missense variants. Our LOF versus GOF prediction corresponded to molecular LOF versus GOF effects for 87 functionally tested variants in SCN1/2/8A and CACNA1I (ROC = 0.73) and was validated in exome-wide data from 21,703 cases and 128,957 controls. We showed respective regional clustering of inferred LOF and GOF nucleotide variants across the alignment of the entire gene family, suggesting shared pathomechanisms in the SCNxA/CACNA1x family genes.

Original languageEnglish
JournalScience translational medicine
Issue number556
Publication statusPublished - 12 Aug 2020
Externally publishedYes


  • Calcium Channels
  • Mutation, Missense/genetics
  • Pharmaceutical Preparations
  • Phenotype
  • Sodium


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