Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. NMD-predicted variants resulting in loss of protein function have previously been reported in this gene (ClinVar). (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 36 of 38). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Multiple NMD-predicted variants have previously been reported pathogenic in clinical cases (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in clinical cases (ClinVar). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26673778)

Variant summary: CC2D2A c.4465_4468delGACA (p.Asp1489LysfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.2e-05 in 161732 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CC2D2A causing CC2D2A-Related Disorders, allowing no conclusion about variant significance. c.4465_4468delGACA has been reported in the literature in individuals affected with CC2D2A-Related Disorders (Hanany_2020, Fu_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31964843, 36307859). ClinVar contains an entry for this variant (Variation ID: 210612). Based on the evidence outlined above, the variant was classified as pathogenic.

This is a frameshift variant in the CC2D2A gene (OMIM: 612013). Pathogenic variants in this gene have been associated with autosomal recessive CC2D2A-related disorders. This variant introduces a premature termination codon in exon 35 out of 37 and is expected to result in loss of function, which is a known disease mechanism for CC2D2A in this disorder (PMID: 19777577) (PVS1). This variant has been identified in the compound heterozygous state in at least 2 individuals reported in the published literature (PMID: 26673778, 36307859) (PM3) and has a 0.0339% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/) (PM2). Based on the current evidence, this variant is classified as pathogenic for autosomal recessive CC2D2A-related disorders.

The CC2D2A c.4465_4468delGACA variant is predicted to result in a frameshift and premature protein termination (p.Asp1489Lysfs*15). This variant has been reported in a patient with nephronophthisis-related ciliopathy (Schueler et al 2016. PubMed ID: 26673778). This variant has also previously been identified in a patient with Meckel-Gruber syndrome (Schueler et al. 2016. PubMed ID: 26673778) and in a fetus with features of Joubert syndrome (Additional file 2, Table S3, Fu et al. 2022. PubMed ID: 36307859). Frameshift variants in CC2D2A are expected to be pathogenic. This variant is interpreted as pathogenic.

NM_001080522.2(CC2D2A):c.4465_4468delGACA(D1489Kfs*15) is a frameshift variant classified as pathogenic in the context of CC2D2A-related disorders. D1489Kfs*15 has been observed in cases with relevant disease (PMID: 26673778, 36307859). Relevant functional assessments of this variant are not available in the literature. D1489Kfs*15 has been observed in referenced population frequency databases. In summary, NM_001080522.2(CC2D2A):c.4465_4468delGACA(D1489Kfs*15) is a frameshift variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Null variant in a gene where loss of function (LOF) is a known mechanism of disease.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.

This sequence change creates a premature translational stop signal (p.Asp1489Lysfs*15) in the CC2D2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CC2D2A are known to be pathogenic (PMID: 19777577). This variant is present in population databases (rs797045437, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with nephronophthisis and Meckel-Gruber syndrome (PMID: 26673778). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 210612). For these reasons, this variant has been classified as Pathogenic.