ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000008.10) (NC_000008.11)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

The CPA6 gene encodes a propeptidase protein that, when cleaved to its active form, functions to remove hydrophobic C-terminal amino acids from peptides in the extracellular matrix. Pathogenic variants in the CPA6 gene are primarily associated with temporal lobe epilepsy and febrile seizures. Lee et al. 2018 (PMID 29924869) discovered a pathogenic frameshift variant in exon 1 leading to a stop codon in exon 1 of 11. The patient had a diagnosis of juvenile myoclonic epilepsy. It is unclear whether this variant was inherited or de novo, but a haploinsufficient mechanism is likely given the location of the variant. Per the authors: "The CPA6 variant was present in the patient along with three other variants. Two were classified as VUS's and one was a likely pathogenic variant in CACN1AH. Review of the criteria used to score the CACN1AH variant as likely path, as well as our personal experience with this gene, led us to believe that the CPA6 variant is the causative variant for this patient." Since inheritance is unknown, the pLI score is 0, and the contributions of the other variants detected in this patient are unclear, we are giving this a haploinsufficiency score of 0.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

DGV shows one large duplication including CPA6 and ARFGEF1 (esv2752263).