rs773881370
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_Very_StrongPM2PP5_Very_Strong
The NM_001378615.1(CC2D2A):c.2999A>T(p.Glu1000Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000272 in 1,435,906 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.
Frequency
Consequence
NM_001378615.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CC2D2A | NM_001378615.1 | c.2999A>T | p.Glu1000Val | missense_variant | 23/37 | ENST00000424120.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CC2D2A | ENST00000424120.6 | c.2999A>T | p.Glu1000Val | missense_variant | 23/37 | 5 | NM_001378615.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152230Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000238 AC: 5AN: 209746Hom.: 0 AF XY: 0.0000176 AC XY: 2AN XY: 113906
GnomAD4 exome AF: 0.0000280 AC: 36AN: 1283558Hom.: 0 Cov.: 19 AF XY: 0.0000280 AC XY: 18AN XY: 643994
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152348Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74516
ClinVar
Submissions by phenotype
Joubert syndrome 9 Pathogenic:1Uncertain:1
Uncertain significance, flagged submission | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Oct 30, 2018 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP5. - |
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1000 of the CC2D2A protein (p.Glu1000Val). This variant is present in population databases (rs773881370, gnomAD 0.003%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 26310553). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217604). 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 not expected to disrupt CC2D2A protein function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at