rs886940102
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3
The NM_001378615.1(CC2D2A):c.4583G>A(p.Arg1528His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1528C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001378615.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CC2D2A | NM_001378615.1 | c.4583G>A | p.Arg1528His | missense_variant | 36/37 | ENST00000424120.6 | |
CC2D2A | NM_001080522.2 | c.4583G>A | p.Arg1528His | missense_variant | 37/38 | ||
CC2D2A | NM_001378617.1 | c.4436G>A | p.Arg1479His | missense_variant | 34/35 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CC2D2A | ENST00000424120.6 | c.4583G>A | p.Arg1528His | missense_variant | 36/37 | 5 | NM_001378615.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152138Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248706Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134932
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461094Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4AN XY: 726842
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152138Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74320
ClinVar
Submissions by phenotype
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 11, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1528 of the CC2D2A protein (p.Arg1528His). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 27081510, 31964843, 34194672). ClinVar contains an entry for this variant (Variation ID: 597406). 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) performed at Invitae indicates that this missense variant is expected to disrupt CC2D2A protein function with a positive predictive value of 80%. This variant disrupts the p.Arg1528 amino acid residue in CC2D2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18950740). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 17, 2023 | Variant summary: CC2D2A c.4583G>A (p.Arg1528His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248706 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4583G>A has been reported in the literature in at least one individual affected with a Joubert syndrome-related disorder (e.g., Ben-Salem_2014, Ben-Salem_2015) as well as an individual with polydactyly (e.g., Zu_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) have cited the variant: one submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. In addition, p.R1528C has been reported as pathogenic in ClinVar and to associate with Joubert syndrome (HGMD database). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 31, 2018 | - - |
CC2D2A-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 17, 2023 | The CC2D2A c.4583G>A variant is predicted to result in the amino acid substitution p.Arg1528His. This variant was previously reported, in the compound heterozygous state with a protein-truncating variant, in an individual who presented with Joubert syndrome (Ben-Salem et al. 2014. PubMed ID: 27081510); a different amino acid substitution at this position (p.Arg1528Cys) was also reported in the same study in two affected individuals. This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-15601238-G-A). Although we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at