The current global epidemiology of SARS-CoV-2 is characterized by a predominance of the Delta variant. Of 839 119 sequences uploaded to GISAID database with specimens collected in the last two months, more than 99.8% are Delta variant . Liu et al. found that the binding affinity between R452/K478-RBD of Delta (B. variant and ACE2 is ~2 times higher than that of wild type (WT) RBD and ACE2 nM) . Therefore, the viral mutation may have high risk of increasing transmissibility and virulence or decreasing of effectiveness of therapeutics, making it more difficult to control the epidemic situation effectively. SARS-CoV-2 variant Omicron (B.1.1.529) was newly announced by the World Health Organization (WHO) on November 26, 2021. Astonishingly, this variant carries as many as 30 single point mutations, 3 deletion mutation and one insertion mutation on spike protein, the main antigenic target of many monoclonal antibodies . Among the mutations, 15 of them are on receptor-binding domain (RBD), especially 10 mutations are in the receptor-binding motif (RBM), which can interact directly with the angiotensin-converting enzyme 2 (ACE2) entry receptor on host membranes when the virus infects host cells . In comparison, other detrimental variants have less than 5 RBD mutations . For example, Delta (B.1.617.2) only has 2 mutations (L452R and T478K) or an additional E484K mutation in the RBM. Therefore, it is speculated that Omicron variant may significantly impact the effectiveness of current prophylactic and/or therapeutic drugs and binding affinity to ACE2. Consequently, Omicron mutant has aroused wide concern and many countries have taken measures on entry restrictions to prevent its rapid spread. Bloom et al. systematically changed every single amino acid in the RBD of the spike protein and determine the effects of the substitutions on ACE2 binding . By checking the 15 Omicron RBD mutations, it was found that 9 single mutations (S371L, S373P, S375F, K417N, G446S, E484A, G496S, Q498R, Y505H) should decrease the binding affinity to ACE2 while 6 mutations (G339D, N440K, S477N, T478K, Q493K, N501Y) might increase the binding affinity to ACE2. However, different from Alpha, Beta, Gamma and Delta variants, Omicron have much more mutations, making the predictions for ACE2 binding and immune evasion very difficult due to the combinatorial mutations, particularly considering that 10 mutations crowded in the RBM interacting with each other.