There actually are already some major ones already; California, Texas, Oregon and Washington (Cascadia), Lakotah, New England, Vermont, Alaska, Hawaii, Puerto Rico, and the former CSA. New Hampshire has one too.
I don't know if I would call any of those U.S. examples major… The other examples on here have had either active separatism or a referendum with resulting supporting or came close to supporting independence.
Technically in Georgia, Azerbaijan, and Somalia the separatists kind of already got their ways. Those regions as of right now act independent from Georgia, Azerbaijan, and Somalia.