chr4-15559183-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001378615.1(CC2D2A):c.2848C>T(p.Arg950Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000226 in 1,549,740 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
CC2D2A
NM_001378615.1 stop_gained
NM_001378615.1 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.88
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-15559183-C-T is Pathogenic according to our data. Variant chr4-15559183-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15559183-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CC2D2A | NM_001378615.1 | c.2848C>T | p.Arg950Ter | stop_gained | 22/37 | ENST00000424120.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CC2D2A | ENST00000424120.6 | c.2848C>T | p.Arg950Ter | stop_gained | 22/37 | 5 | NM_001378615.1 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152072Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000623 AC: 1AN: 160490Hom.: 0 AF XY: 0.0000119 AC XY: 1AN XY: 83954
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GnomAD4 exome AF: 0.0000229 AC: 32AN: 1397668Hom.: 0 Cov.: 29 AF XY: 0.0000247 AC XY: 17AN XY: 689442
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152072Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74264
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 20, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 22, 2023 | Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26092869, 27959436, 31618753, 18950740) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 22, 2023 | PM2, PS4_moderate, PVS1 - |
Joubert syndrome 9 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2008 | - - |
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 | Sep 17, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 745). This premature translational stop signal has been observed in individuals with clinical features of Joubert syndrome (PMID: 18950740, 27959436, 31618753). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg950*) 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). - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 10, 2017 | - - |
CC2D2A-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 12, 2023 | The CC2D2A c.2848C>T variant is predicted to result in premature protein termination (p.Arg950*). This variant has been reported in individuals with Joubert syndrome (Gorden et al 2008. PubMed ID: 18950740; Xiao D et al 2016. PubMed ID: 27959436; Table S1, Ziats MN et al 2019. PubMed ID: 31618753). This variant is reported in 0.0041% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-15560806-C-T). Nonsense variants in CC2D2A are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at