I ended up in this situation several times with my .NET 4.6.1 web site. I created the problem each time when I added a reference to a separate .NET Core project. Upon building, Visual Studio correctly alerted me that such cross-framework references are invalid, and I quickly deleted the project reference. The project built fine after that, but the System.Runtime error appeared when accessing the web site and refused to go away.
The fix each time was lame but effective: I deleted the project directory and redownloaded it from source control. Even though there was no difference between before and after, I was able to build the project and access the page with no complaints.