ClinVar Miner

Submissions for variant NM_017721.5(CC2D1A):c.1357-2A>C

gnomAD frequency: 0.00164  dbSNP: rs200557641
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002314394 SCV000847905 benign Inborn genetic diseases 2023-12-18 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV000889161 SCV001032823 likely benign not provided 2024-01-31 criteria provided, single submitter clinical testing
GeneDx RCV000889161 SCV001988021 uncertain significance not provided 2019-08-05 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge
Centogene AG - the Rare Disease Company RCV001809779 SCV002059686 uncertain significance Intellectual disability, autosomal recessive 3 2019-05-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003387918 SCV004099660 uncertain significance not specified 2023-09-08 criteria provided, single submitter clinical testing Variant summary: CC2D1A c.1357-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site and three predict the variant strengthens/creates a 3' acceptor site located three nucleotides downstream, which if used, is expected to result in the in-frame deletion of one amino acid (Gln453) from the coding sequence. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00052 in 260974 control chromosomes, predominantly at a frequency of 0.0053 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote, suggesting it could be a benign polymorphism found primarily in individuals of African or African-American ancestry. To our knowledge, no occurrence of c.1357-2A>C in individuals affected with Intellectual Disability 3 and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Three submitters classified the variant as VUS and one submitter classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

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