Submissions for variant NM_001378615.1(CC2D2A):c.3076A>G (p.Lys1026Glu)

gnomAD frequency: 0.00001  dbSNP: rs759702917

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414440	SCV000492186	uncertain significance	not specified	2016-11-25	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CC2D2A gene. The K1026E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K1026E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001361910	SCV001557903	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2022-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1026 of the CC2D2A protein (p.Lys1026Glu). This variant is present in population databases (rs759702917, gnomAD 0.006%). 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: 373581). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CC2D2A protein function. 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.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783780	SCV005397672	uncertain significance	Joubert syndrome 9	2024-05-23	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (A>G) at position 3076 of the coding sequence of the CC2D2A gene that results in a lysine to glutamic acid amino acid change at residue 1026 of the coiled-coil and C2 domain containing 2A protein. This residue falls in the C2 domain (UniProt) which is predicted to be involved in calcium-dependent membrane targeting (PMID: 18387594). This is a previously reported variant (ClinVar 373581) that has not been observed in individuals affected by CC2D2A-related disorders in the published literature, to our knowledge. This variant is present in 6 of 1609750 alleles (0.0013%) in the gnomAD v4.1.0 population dataset. Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Lys1026 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM2, PP3