I'd personally recommend you going to a gun range with lots of rentals and look around.
I don't know what kind of build your wife is, but my girl is scrawny, like 105 lbs. Anyways, she doesn't care for semi autos that much cuz of recoil, but can handle my Ruger GP100 5in with .38s in it. In fact, it is now my new home defense pistol since both of us can shoot it and .38 personal defense rounds are pretty mean.
There is alot to consider when buying a handgun, but what it really comes down to is what will work for you if something happens. So make sure you try out several different types. And like someone stated earlier, spend time practicing, it makes a world of difference.
Springfield, Glock, Sig, Kimber semis, and Ruger, Taurus, Smith and Wesson revolvers are my favorites. As far as calibers go I'd say anywhere between .380 and .40 is all you will need. If you go with a .380, PD rounds are a most IMO, but other than that, they are just fine.
Based off of your budget and needs, I'd say a Taurus or Ruger revolver in .357 so that you can swithch between the .38s and .357 magnums. They go for around $350-$400. Easy to use, reliable, and fun to shoot too.
Also, for a safe, get the finger print or key code. Don't have to worry about the little one finding keys on accident.
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