Germline variants of ten keratin genes (K1, K2, K5, K6A, K6B, K9, K10, K14, K16, and K17) have been reported for causing different types of genodermatoses with an autosomal dominant mode of inheritance. Among all the variants of these ten keratin genes, most of them are missense variants. Unlike pathogenic and likely pathogenic variants, understanding the clinical importance of novel missense variants or variants of uncertain significance (VUS) is the biggest challenge for clinicians or medical geneticists. Functional characterization is the only way to understand the clinical association of novel missense variants or VUS but it is time consuming, costly, and depends on the availability of patient’s samples. Existing databases report the pathogenic variants of the keratin genes, but never emphasize the systematic effects of these variants on keratin protein structure and genotype-phenotype correlation. To address this need, we developed a comprehensive database KVarPredDB, which contains information of all ten keratin genes associated with genodermatoses. We integrated and curated 400 reported pathogenic missense variants as well as 4629 missense VUS. KVarPredDB predicts the pathogenicity of novel missense variants as well as to understand the severity of disease phenotype, based on four criteria; firstly, the difference in physico-chemical properties between the wild type and substituted amino acids; secondly, the loss of inter/intra-chain interactions; thirdly, evolutionary conservation of the wild type amino acids and lastly, the effect of the substituted amino acids in the heptad repeat. Molecular docking simulations based on resolved crystal structures were adopted to predict stability changes and get the binding energy to compare the wild type protein with the mutated one. We use this basic information to determine the structural and functional impact of novel missense variants on the keratin coiled-coil heterodimer. KVarPredDB was built under the integrative web application development framework SSM (SpringBoot, Spring MVC, MyBatis) and implemented in Java, Bootstrap, React-mutation-mapper, MySQL, Tomcat. The website can be accessed through http://bioinfo.zju.edu.cn/KVarPredDB . The genomic variants and analysis results are freely available under the Creative Commons license. KVarPredDB provides an intuitive and user-friendly interface with computational analytical investigation for each missense variant of the keratin genes associated with genodermatoses.

中文翻译：

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KVarPredDB：用于预测与遗传性皮肤病相关的角蛋白基因错义序列变异的致病性的数据库

据报道，十种角蛋白基因（K1、K2、K5、K6A、K6B、K9、K10、K14、K16 和 K17）的种系变异会导致不同类型的具有常染色体显性遗传模式的基因性皮肤病。在这十个角蛋白基因的所有变体中，大部分是错义变体。与致病性和可能的​​致病性变异不同，了解新的错义变异或意义不明的变异 (VUS) 的临床重要性是临床医生或医学遗传学家面临的最大挑战。功能表征是了解新型错义变异或 VUS 临床关联的唯一方法，但它既费时又费钱，并且取决于患者样本的可用性。现有数据库报告了角蛋白基因的致病变异，但从不强调这些变体对角蛋白结构和基因型-表型相关性的系统影响。为了满足这一需求，我们开发了一个综合数据库 KVarPredDB，其中包含与遗传性皮肤病相关的所有 10 个角蛋白基因的信息。我们整合并整理了 400 个报告的致病性错义变异以及 4629 个错义 VUS。KVarPredDB 基于四个标准预测新错义变异的致病性并了解疾病表型的严重程度；第一，野生型和取代氨基酸的理化性质差异；其次，链间/链内相互作用的丧失；第三，野生型氨基酸的进化保守性，最后，七肽重复序列中被取代氨基酸的影响。采用基于解析晶体结构的分子对接模拟来预测稳定性变化并获得结合能以比较野生型蛋白质与突变型蛋白质。我们使用此基本信息来确定新型错义变体对角蛋白卷曲螺旋异二聚体的结构和功能影响。KVarPredDB 是在集成的 Web 应用程序开发框架 SSM（SpringBoot、Spring MVC、MyBatis）下构建的，并在 Java、Bootstrap、React-mutation-mapper、MySQL、Tomcat 中实现。该网站可通过 http://bioinfo.zju.edu.cn/KVarPredDB 访问。基因组变异和分析结果在知识共享许可下免费提供。