rs118204051
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_001378615.1(CC2D2A):c.3364C>T(p.Pro1122Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,510 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).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
CC2D2A
NM_001378615.1 missense
NM_001378615.1 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 7.63
Genes affected
CC2D2A (HGNC:29253): (coiled-coil and C2 domain containing 2A) This gene encodes a coiled-coil and calcium binding domain protein that appears to play a critical role in cilia formation. Mutations in this gene cause Meckel syndrome type 6, as well as Joubert syndrome type 9. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.9
PP5
Variant 4-15567752-C-T is Pathogenic according to our data. Variant chr4-15567752-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 743.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=4}. Variant chr4-15567752-C-T is described in Lovd as [Likely_pathogenic]. Variant chr4-15567752-C-T is described in Lovd as [Pathogenic]. Variant chr4-15567752-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CC2D2A | NM_001378615.1 | c.3364C>T | p.Pro1122Ser | missense_variant | Exon 26 of 37 | ENST00000424120.6 | NP_001365544.1 | |
| CC2D2A | NM_001080522.2 | c.3364C>T | p.Pro1122Ser | missense_variant | Exon 27 of 38 | NP_001073991.2 | ||
| CC2D2A | NM_001378617.1 | c.3217C>T | p.Pro1073Ser | missense_variant | Exon 24 of 35 | NP_001365546.1 | ||
| LOC124900671 | XR_007058061.1 | n.130+2979G>A | intron_variant | Intron 1 of 1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000426 AC: 1AN: 234830Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 127542
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GnomAD4 exome AF: 0.00000138 AC: 2AN: 1448510Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1AN XY: 720208
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GnomAD4 genome
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Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:9Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Joubert syndrome 9 Pathogenic:5Uncertain:1
| Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2008 | - - |
| Likely pathogenic, criteria provided, single submitter | research | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Mar 17, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Aug 25, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The homozygous p.Pro1122Ser variant in CC2D2A was identified by our study in one individual with Joubert syndrome. The p.Pro1122Ser variant in CC2D2A has been reported in at least 5 Saudi Arabian individuals with Joubert syndrome (PMID: 26092869, 18950740), and has been identified in 0.01951% (1/5126) of other chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although there is some suspicion of pathogenicity, the clinical significance of the p.Pro1122Ser variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PM1_Supporting (Richards 2015). - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
not provided Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 17, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 28, 2017 | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 10, 2022 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1122 of the CC2D2A protein (p.Pro1122Ser). This variant is present in population databases (rs118204051, gnomAD no frequency). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 18950740). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 743). 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. For these reasons, this variant has been classified as Pathogenic. - |
COACH syndrome 1 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 14, 2019 | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing by following sources [PMID: 29620724, 18950740, ClinVar ID: 743] - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;.
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Loss of glycosylation at P1122 (P = 0.0238);Loss of glycosylation at P1122 (P = 0.0238);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at