I am not sure whether there is a single rule that fits all projects but a good guide would be: choose an early exon (like 2 or 3), choose an exon that is present in all splice variants, take care that your mutant transcript will contain a stop codon, that will send the mRNA to nonsense mediated mRNA decay (NMD). For the last point see this text copied from Wikipedia (NMD): "In vertebrates, the location of the last exon-junction complex relative to the termination codon usually determines whether the transcript will be subjected to NMD or not. If the termination codon is downstream of or within about 50 nucleotides of the final exon-junction complex then the transcript is translated normally. However, if the termination codon is further than about 50 nucleotides upstream of any exon-junction complexes, then the transcript is down regulated by NMD". Good luck with your knockout.

I think you should use the one which will not be affected by alternative spicing

I remember Dr Vakoc said in his seminar that you should target exons encoding functional domains such as bromo, SET and so on. Maybe this paper would be of some help: PMID: 25961408.

I am not sure whether there is a single rule that fits all projects but a good guide would be: choose an early exon (like 2 or 3), choose an exon that is present in all splice variants, take care that your mutant transcript will contain a stop codon, that will send the mRNA to nonsense mediated mRNA decay (NMD). For the last point see this text copied from Wikipedia (NMD): "In vertebrates, the location of the last exon-junction complex relative to the termination codon usually determines whether the transcript will be subjected to NMD or not. If the termination codon is downstream of or within about 50 nucleotides of the final exon-junction complex then the transcript is translated normally. However, if the termination codon is further than about 50 nucleotides upstream of any exon-junction complexes, then the transcript is down regulated by NMD". Good luck with your knockout.

Thanks for your answers!