ClinVar Miner

Submissions for variant NM_001170629.2(CHD8):c.3308-1G>C

dbSNP: rs1888129073
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Kids Neuroscience Centre, Sydney Children's Hospitals Network RCV001726500 SCV001571519 pathogenic Intellectual developmental disorder with autism and macrocephaly criteria provided, single submitter clinical testing mRNA studies confirm the c.3308-1G>C variant induces abnormal splicing of CHD8 transcripts in mRNA derived from blood. We detect two abnormal splicing events: (1) Use of a cryptic 3’-splice site within intron 15 (r.3307_3308ins[3308-66_3308-1;g>c]; p.(Gly1103Valfs*3)), (2) Use of a cryptic 3’-splice site within exon 16 (r.3308_3379del; p.(Ala1104Hisfs*12)) Both events induce a frameshift and encode a premature termination codon. These transcripts are predicted to be targeted by nonsense-mediated decay (NMD). Any mis-spliced CHD8 transcripts that escape NMD encode CHD8 protein lacking 1,477 amino acids from the C-terminus, removing the C-terminal helicase and BRK domains. Frameshift and nonsense variants in CHD8 are commonly reported in ClinVar as pathogenic variants. Therefore, use of the cryptic 3’-splice sites induced by the c.3308-1G>C variant, inducing a frameshift, is consistent with the known pathogenetic mechanism in CHD8 related intellectual disability.

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