Introduction: COVID-19 is an acute viral illness caused by severe acute respiratory syndrome corona virus 2(SARS-CoV-2). Since the onset of the SARS-CoV-2 pandemic, multiple new variants of concern have emerged which are associated with enhanced transmissibility and increased virulence. It also highlights the role of the clinical inter professional teams, public health agencies, and community participation in improving patient care. Aim: An analysis of genomic sequencing variants of SARS-CoV-2 in symptomatic patients during 2nd and 3rd wave of pandemic by next-generation sequencing (NGS). Materials And Methods: A total of 200 symptomatic patients, throat/nasopharyngeal swab were collected for real-time reverse transcription-polymerase chain reactions (RT-PCR) at tertiary care hospital, Guntur. The specimens were transported under cold chain according to guidelines to Centre for Cellular & Molecular biology (CCMB), Hyderabad, for genome sequence analysis by next generation sequencing (NGS). Study period – 2ndwave i.e., MARCH 2021 –NOVEMBER 2021 & 3rdwave i.e., DECEMBER 2021 –MARCH 2022 according to WHO. Result – Out of 200 samples analysed, 132 samples of 2nd wave & 68 samples in 3rd wave. Out of 132 samples, 57 Delta (B.1.617.2), 75 Delta sub-lineages. Out of 68 samples 41 Omicron (B.1.1.529), 11 Omicron lineages (BA.1), 16 Omicron (BA.2). Conclusion: During the 2ndwave the symptomatic patients were detected with more delta and delta sub lineages showing high mortality rate. During 3rdwave omicron and omicron sub lineages were detected more than delta showing very high transmissibility and less mortality. Continuous monitoring and analysis of the sequence variants to understand the genetic heterogenicity.