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• The study covered 7457 SARS-CoV-2 positive samples from 16 Indian states, with 3002 samples passing the sequencing quality control criteria, making it the most comprehensive genomic surveillance for the region. • The study identified 104 different SARS-CoV-2 pango-lineages classified into 19 clades, revealing the diversity of virus variants circulating in the region. • The month-wise dynamics of SARS-CoV-2 over two years clearly showed a transition from the Delta variant to the Omicron variant in January 2022. • The analysis identified eight mutations of interest, including L18F, K417N, K417T, L452R, S477N, N501Y, P681H, P681R, and the mutation of concern E484K in the spike glycoprotein region. Reading the viral genome through whole genome sequencing (WGS) enables the detection of changes in the viral genome. The rapid changes in the SARS-CoV-2 viral genome may cause immune escape leading to an increase in the pathogenicity or infectivity. Monitoring mutations through genomic surveillance helps understand the amino acid changes resulting from the mutation. These amino acid changes, especially in the spike glycoprotein, may have implications on the pathogenicity of the virus by rendering it immune-escape. The region of Vidarbha in Maharashtra represents 31.6 % of the state's total area. It holds 21.3 % of the total population. In total, 7457 SARS-CoV-2 positive samples belonging to 16 Indian States were included in the study, out of which 3002 samples passed the sequencing quality control criteria. The metadata of 7457 SARS-CoV-2 positive samples included in the study was sourced from the Integrated Health Information Platform (IHIP). The metadata of 3002 sequenced samples, including the FASTA sequence, was submitted to the Global Initiative on Sharing Avian Influenza Data (GISAID) and the Indian biological data centre (IBDC). This study identified 104 different SARS-CoV-2 pango-lineages classified into 19 clades. We have also analysed the mutation profiles of the variants found in the study, which showed eight mutations of interest, including L18F, K417N, K417T, L452R, S477N, N501Y, P681H, P681R, and mutation of concern E484K in the spike glycoprotein region. The study was from November 2020 to December 2022, making this study the most comprehensive genomic surveillance of SARS-CoV-2 conducted for the region. [ABSTRACT FROM AUTHOR]