ClinVar Miner

Submissions for variant NM_014141.6(CNTNAP2):c.3010G>A (p.Asp1004Asn)

gnomAD frequency: 0.00001  dbSNP: rs748508785
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520214 SCV000621123 uncertain significance not provided 2023-03-30 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV000552031 SCV000645099 uncertain significance Cortical dysplasia-focal epilepsy syndrome 2022-08-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1004 of the CNTNAP2 protein (p.Asp1004Asn). This variant also falls at the last nucleotide of exon 18, which is part of the consensus splice site for this exon. This variant is present in population databases (rs748508785, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CNTNAP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 452326). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000767939 SCV000898624 uncertain significance Autism, susceptibility to, 15; Cortical dysplasia-focal epilepsy syndrome 2022-09-15 criteria provided, single submitter clinical testing CNTNAP2 NM_014141.5 exon 18 p.Asp1004Asn (c.3010G>A):This variant has not been reported in the literature but is present in 2/17248 East Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs748508785). This variant is present in ClinVar (Variation ID:452326). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, this variant occurs in the last nucleotide of the exon; however, computational prediction tools do not suggest that it may alter splicing. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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