RYR2 and cancer: First, RYRs are not known driver genes of cancer; Secondly, although the mutational frequency of RYR ranked high in some cancers, most mutations appeared to be randomly distributed, possibly due to accumulation of DNA repair mistakes; Thirdly, significant correlation was identified between RYR mutations and TMB; Fourthly, similar mutational pattern and frequency can also be observed in other large proteins of calcium signaling compared with RYR, such as those illustrated in Supplementary Fig. 1.