TITINdb2-expanding annotation and structural information for protein variants in the giant sarcomeric protein titin.

Summary: We present TITINdb2, an update to the TITINdb database previously constructed to facilitate the identification of pathogenic missense variants in the giant protein titin, which are associated with a variety of skeletal and cardiac myopathies. The database and web portal have been substantially revised and include the following new features: (i) an increase in computational annotation from 4 to 20 variant impact predictors, available through a new custom data table dialogue; (ii) through structural coverage of single domains with AlphaFold2 predicted models; (iii) newly predicted domain-domain interface annotations; (iv) an expanded in silico saturation mutagenesis incorporating four variant impact predictors; (v) a comprehensive overhaul of available data, including population data sources and variants reported pathogenic in the literature; and (vi) a curated mapping of existing protein, transcript, and chromosomal sequence positions and a new variant conversion tool to translate variants in one format to any other format.

Availability and implementation: The database is accessible via titindb.kcl.ac.uk/TITINdb/.