A 12-column grid is popular because it divides neatly into halves, thirds and quarters. That flexibility is also why so many pages built on it look alike.
Start from the content
Measure your most important element first: the ideal line length of body text, the aspect ratio of your images, the width of a data table. Build columns around those, not the other way round.
Try asymmetry on purpose
A 5 + 7 split or a narrow margin column for notes and captions immediately gives a page character. Asymmetric grids suit editorial content where hierarchy matters.
Let the grid break once
- One image that bleeds to the edge.
- One headline that ignores the column.
- One pull quote in the margin.
A grid is most noticeable, and most useful, at the single moment you choose to break it.