The fall of 2020 brought several new variants of SARS-CoV-2 circulating across the globe, and the steadily increasing COVID-19 cases are responsible for the emergence of these variants. All the SARS-CoV-2 variants reported to date have multiple mutations in the spike (S) protein, specifically in the receptor-binding domain (RBD). Here, we employed an integrated computational approach involving structure and sequence based predictions to study the effect of naturally occurring variations in the S-RBD on its stability and ACE2 binding affinity. The hotspot stabilizing residue mutations N501I, N501Y, Q493L, Q493H and K417R, strengthen the RBD-ACE2 complex by modulating the interaction statistics at the interface. Thus, we report here some critical mutations that could increase the binding affinity of the SARS-CoV-2 RBD with ACE2, increasing the viral infectivity and pathogenicity. Understanding the effect of these mutations will help in developing potential vaccines and therapeutics.