When replying to a comment, start with the same common sense and basic etiquette that you would apply
in your daily life if you were not a terrible person. If you wrote the original comment, what would you like from people replying to your comment?
First, if you had spent some time and energy crafting a clever joke, you probably wouldn't want someone to come along and explain the punchline. It implies that the original poster himself missed the joke and that the it took the super genius who is rolling around later to unscramble it for him. Your role as a commenter isn't to be a humor_ninja and explain to people how they could have made their joke funnier: it's to make a funny joke of your own. If you're in the slow reading group, this clip from what-I'm-sure-is-your-favorite-show will help.
Second, if done sloppily, a reply can ruin a joke that is deliberately subtle. True Story: When I was a newly minted commenter, and didn’t know my way around very well, one of the most respected senior commenters posted a joke. I read it, and chuckled, but then I realized something: there was a much funnier joke that tied perfectly to his joke, just sitting there waiting to get made. I spent about 3 seconds writing it out and pressed submit. Almost immediately, I cringed. There was no way that this vastly superior commenter had overlooked a joke that took me only moments to stumble on. No, he’d intentionally left that secondary joke unsaid so that clever readers could each make the connection themselves, thereby making his original joke all the funnier. All I had done was to effectively explain his latent joke, thereby robbing it of its masterful subtlety. Then, something happened that made it even worse: I looked back up at the screen and saw that I had received a +1 for my reply. It was a +1 that rightfully belonged to the original commenter, not to mention that he probably lost several others when I’d stepped all over his joke. I still feel sick when I think about that decision, and I resolved that I would never do anything like that again (history will record that I didn’t keep that promise, but it’s not from a lack of trying).
Now, one of those disclaimers I was talking about, this is not to say that replies that *look* like explanations never work. They can be very funny if they're done as actual jokes, and not solely as an explanation for a pre-existing joke.
Another thing to be careful of is making a recontextualization out of another person's comment. It can easily turn into a form of thread jacking. There are some obvious exceptions, usually when the original comment is sort of a bust due to an image save fail, redaction, or something like that, but it’s dangerous territory. If you don’t do it just right, you’re basically saying, “hey, ignore the original joke someone put some hard work into, and just focus on how the words they chose to use might be funny in a different context.” Except they rarely are as funny as the original joke, and you’ve now pissed all over someone else’s work. Remember, once you inject something like that into a thread, the odds are additional readers might pay more attention to your reply than to the original comment. How would that make you feel as the original commenter?