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. Here, RYR1 is linked to cancer.