4-15563395-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001378615.1(CC2D2A):c.3055C>T(p.Arg1019*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000591 in 1,606,748 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000056 ( 0 hom. )
Consequence
CC2D2A
NM_001378615.1 stop_gained
NM_001378615.1 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.82
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]
Genome browser will be placed here
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 4-15563395-C-T is Pathogenic according to our data. Variant chr4-15563395-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15563395-C-T is described in Lovd as [Pathogenic]. Variant chr4-15563395-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CC2D2A | NM_001378615.1 | c.3055C>T | p.Arg1019* | stop_gained | 24/37 | ENST00000424120.6 | NP_001365544.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CC2D2A | ENST00000424120.6 | c.3055C>T | p.Arg1019* | stop_gained | 24/37 | 5 | NM_001378615.1 | ENSP00000403465.1 |
Frequencies
GnomAD3 genomes 0.0000920 AC: 14AN: 152154Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
14
AN:
152154
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000102 AC: 24AN: 236182Hom.: 0 AF XY: 0.0000940 AC XY: 12AN XY: 127678
GnomAD3 exomes
AF:
AC:
24
AN:
236182
Hom.:
AF XY:
AC XY:
12
AN XY:
127678
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000557 AC: 81AN: 1454594Hom.: 0 Cov.: 31 AF XY: 0.0000650 AC XY: 47AN XY: 722708
GnomAD4 exome
AF:
AC:
81
AN:
1454594
Hom.:
Cov.:
31
AF XY:
AC XY:
47
AN XY:
722708
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.0000920 AC: 14AN: 152154Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74322
GnomAD4 genome
AF:
AC:
14
AN:
152154
Hom.:
Cov.:
33
AF XY:
AC XY:
6
AN XY:
74322
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
1
ALSPAC
AF:
AC:
0
ESP6500AA
AF:
AC:
1
ESP6500EA
AF:
AC:
2
ExAC
AF:
AC:
12
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Joubert syndrome 9 Pathogenic:3
| Pathogenic, criteria provided, single submitter | research | Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL) | Apr 27, 2023 | - - |
| Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 28, 2021 | - - |
not provided Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CC2D2A p.R1019* variant was identified in the heterozygous or compound heterozygous state in 4 of 194 families with Joubert syndrome and related disorders (Gorden_2008_PMID:18950740; Bachmann-Gagescu_2012_PMID:22241855). The variant was identified in dbSNP (ID: rs370880399) and ClinVar (classified as pathogenic by Invitae, GeneDx, Fulgent Genetics, UW Hindbrain Malformation Research Program, University of Washington and as likely pathogenic by Illumina). The variant was identified in control databases in 26 of 267576 chromosomes at a frequency of 0.00009717 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 14 of 10098 chromosomes (freq: 0.001386), Other in 2 of 6912 chromosomes (freq: 0.000289), African in 2 of 23072 chromosomes (freq: 0.000087), Latino in 2 of 33894 chromosomes (freq: 0.000059), European (non-Finnish) in 5 of 121798 chromosomes (freq: 0.000041) and South Asian in 1 of 28914 chromosomes (freq: 0.000035), but was not observed in the East Asian or European (Finnish) populations. The c.3055C>T variant leads to a premature stop codon at position 1019 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the CC2D2A gene are an established mechanism of disease in Joubert syndrome and related disorders and is the type of variant expected to cause the disorder when found in the homozygous or compound heterozygous state. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 12, 2024 | 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; This variant is associated with the following publications: (PMID: 25525159, 27081510, 19466712, 22241855, 26092869, 31589614, 33486889, 18950740, 29165578, 31964843) - |
CC2D2A-related disorder Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 30, 2018 | The CC2D2A c.3055C>T (p.Arg1019Ter) variant is a stop-gained variant that is predicted to cause premature truncation of the protein. This variant has been identified in at least four probands with Joubert syndrome, including in three in a compound heterozygous state with a missense variant and in one in a heterozygous state where a second variant was not detected (Gorden et al. 2008; Bachmann-Gagescu et al. 2012; Bachmann-Gagescu et al. 2015). The p.Arg1019Ter variant has also been reported in a homozygous state as a result of a different nucleotide substitution in one individual with Joubert syndrome (Ben-Salem et al. 2014). Control data are unavailable for this variant which is reported at a frequency of 0.00025 in the total population of the Exome Sequencing Project. Based on the evidence and due to the potential impact of stop-gained variants, the p.Arg1019Ter variant is classified as likely pathogenic for CC2D2A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 14, 2023 | The CC2D2A c.3055C>T variant is predicted to result in premature protein termination (p.Arg1019*). This variant has been reported in multiple individuals with Joubert syndrome (Gorden et al. 2008. PubMed ID: 18950740; Bachmann-Gagescu et al. 2015. PubMed ID: 26092869). We have also detected this variant in the compound heterozygous state in a child with Joubert syndrome (internal data, PreventionGenetics). Taken together, we interpret this variant as pathogenic. - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2024 | This sequence change creates a premature translational stop signal (p.Arg1019*) 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). This variant is present in population databases (rs370880399, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome (PMID: 18950740, 22241855, 26092869, 27082236). ClinVar contains an entry for this variant (Variation ID: 217602). For these reasons, this variant has been classified as Pathogenic. - |
Joubert syndrome 9;C2676790:Meckel syndrome, type 6;C5436837:COACH syndrome 2;C5676970:Retinitis pigmentosa 93 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 20, 2024 | - - |
Joubert syndrome 9;C2676790:Meckel syndrome, type 6;C5435651:COACH syndrome 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
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
Vest4
GERP RS
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