My situation is the same. I use 55g varmint tipped 5.56.What kinds of firearms do you have experience with? What kind of environmental concerns are there? By that, I mean are you in an apartment with thin walls and lots of people around you, or are you in a stand-alone home by yourself? Are you looking for a rifle that you're hunkering down behind a door with or something more compact that allows you to move(like if you'd need to go get your kids for instance). What kind of budget do you have?
I like semiautomatic, short rifles chambered in an intermediate rifle cartridge for HD. Something like a 5.56 tavor, 9" 300blk AR, 14.5" 5.56 AR, etc... give you a lot of capability. I also like 77gr 5.56 or 300 blk BECAUSE it punches through barriers. For my situation, I'm likely to be shooting down from the top of the stairs and don't need to worry as much about overpenetration. I WANT a defensive load that can shoot through a wall/chair/door and still have enough ass to put a threat down. When I lived in apartments, I instead went with varmint-tipped 55 gr loads for 5.56 that more reliably break up through walls and posed less of a risk to neighbors. I don't see a compelling argument for going with a rifle chambered in a handgun cartridge. You gain nothing and lose a lot of terminal performance.