ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

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Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
22495309 O?Roak et al. (2012) describe a male (sample 13606.p1) with sporadic autism spectrum disorder (ASD) who has a nonverbal IQ (NVIQ) of 60 (Table 1). Whole exome sequencing of the affected individual identified a de novo heterozygous nonsense variant in exon 16 of the CDC42BPB gene (Chr14:103434646G>A) (Supplementary Table 3). This variant causes a premature termination at codon 764 of the CDC42BPB protein (p.Arg764*). This variant was not observed in either parent nor in the unaffected female sibling (13606.s1, Supplementary Table 5). Of note, the affected individual also had a de novo heterozygous missense variant in the H2AFV gene (Chr7:44875121G>A, p.Arg81Cys) which was not observed in either parent nor in the unaffected female sibling. However, the nonsense variant in CDC42BPB was identified, per the authors to be a top ASD risk contributing variant based on the deleteriousness of the variant, functional evidence, or previous studies whereas the missense variant in H2AFV was not. In addition, CDC42BPB was mapped to a highly interconnected beta-catenin/chromatin remodeling protein network ranked significantly for autism candidate genes. This variant is absent from gnomAD as of October 2018.
28263302 Yuen et al. (2017) identified a de novo frameshift deletion in the CDC42BPB gene (Chr14:103442072_103442075delCTTT) in an individual with autism spectrum disorder (sample AU079605; Supplementary Table 4). Within this study cohort no other variants in CDC42BPB were observed in any of the other 2,260 autism cases or in any of the 2,573 controls.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.