Submissions for variant NM_001378615.1(CC2D2A):c.4315-6_4315-3del

dbSNP: rs926806639

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001368996	SCV001565422	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2022-07-22	criteria provided, single submitter	clinical testing	This sequence change falls in intron 34 of the CC2D2A gene. It does not directly change the encoded amino acid sequence of the CC2D2A protein. This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CC2D2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1059667). 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.
GeneDx	RCV001574763	SCV001801635	likely pathogenic	not provided	2024-10-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge
Institute of Human Genetics, Heidelberg University	RCV002271646	SCV002556338	likely pathogenic	Meckel syndrome, type 6	2022-03-16	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002271646	SCV003807198	uncertain significance	Meckel syndrome, type 6	2022-05-27	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderated
Clinical Genomics Laboratory, Washington University in St. Louis	RCV005054367	SCV005688768	uncertain significance	Joubert syndrome 9	2024-10-25	criteria provided, single submitter	clinical testing	The CC2D2A c.4315-6_4315-3del variant, to our knowledge, has not been reported in the medical literature. Computational predictors indicate that this variant would alter splicing, evidence that correlates to an impact of this variant's CC2D2A function. This variant is only observed on 1/15,426 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Another variant in the donor motif of the same exon, c.4290+1G>A, has been reported in an affected individual with Joubert syndrome and is considered pathogenic (ClinVar Variation ID: 191188). This variant has been reported in the ClinVar database as a germline likely pathogenic variant by two submitters and a variant of uncertain significance by two submitters. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.
PreventionGenetics, part of Exact Sciences	RCV004531174	SCV004746981	uncertain significance	CC2D2A-related disorder	2023-11-22	no assertion criteria provided	clinical testing	The CC2D2A c.4315-6_4315-3delTCTT variant is predicted to result in an intronic deletion. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.