A method of target enrichment comprising: (a) providing a reaction mixture comprising: (i) a first oligonucleotide primer having a tail domain that is not complementary to a target sequence, the tail domain comprising a first universal primer sequence; a cleavage domain, wherein said cleavage domain, when hybridized to the target, is cleavable by an RNase H2 enzyme, positioned 5' of a blocking group and 3' of a position of variation, the blocking group linked at or near the end of the 3'-end of the first oligonucleotide primer wherein the blocking group prevents primer extension and/or inhibits the first primer from serving as a template for DNA synthesis; (ii) a sample nucleic acid that has been treated with a CRISPR enzyme, which may or may not have the target sequence; (iii) a cleaving enzyme, wherein the cleaving enzyme is an RNase H2 enzyme; and (iv) a polymerase; (b) hybridizing the first primer to the target DNA sequence to form a double-stranded substrate; (c) cleaving the hybridized first primer, if the first primer is complementary to the target, with the cleaving enzyme at a point within or adjacent to the cleavage domain to remove the blocking group from the first primer; and (d) extending the first primer with the polymerase. (a) providing a reaction mixture comprising: (i) a first oligonucleotide primer having a tail domain that is not complementary to a target sequence, the tail domain comprising a first universal primer sequence; a cleavage domain, wherein said cleavage domain, when hybridized to the target, is cleavable by an RNase H2 enzyme, positioned 5' of a blocking group and 3' of a position of variation, the blocking group linked at or near the end of the 3'-end of the first oligonucleotide primer wherein the blocking group prevents primer extension and/or inhibits the first primer from serving as a template for DNA synthesis; (ii) a sample nucleic acid that has been treated with a CRISPR enzyme, which may or may not have the target sequence; (iii) a cleaving enzyme, wherein the cleaving enzyme is an RNase H2 enzyme; and (iv) a polymerase; (i) a first oligonucleotide primer having a tail domain that is not complementary to a target sequence, the tail domain comprising a first universal primer sequence; a cleavage domain, wherein said cleavage domain, when hybridized to the target, is cleavable by an RNase H2 enzyme, positioned 5' of a blocking group and 3' of a position of variation, the blocking group linked at or near the end of the 3'-end of the first oligonucleotide primer wherein the blocking group prevents primer extension and/or inhibits the first primer from serving as a template for DNA synthesis; (ii) a sample nucleic acid that has been treated with a CRISPR enzyme, which may or may not have the target sequence; (iii) a cleaving enzyme, wherein the cleaving enzyme is an RNase H2 enzyme; and (iv) a polymerase; (b) hybridizing the first primer to the target DNA sequence to form a double-stranded substrate; (c) cleaving the hybridized first primer, if the first primer is complementary to the target, with the cleaving enzyme at a point within or adjacent to the cleavage domain to remove the blocking group from the first primer; and (d) extending the first primer with the polymerase. <EOS>