chr4-15601403-CCTCT-C
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM4PP5
The NM_001378615.1(CC2D2A):c.4844_4847del(p.Ser1615LeufsTer16) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,543,904 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
CC2D2A
NM_001378615.1 frameshift
NM_001378615.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.28
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;
PM4
Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 1699 codons.
PP5
Variant 4-15601403-CCTCT-C is Pathogenic according to our data. Variant chr4-15601403-CCTCT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217606.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1, Likely_pathogenic=1}. Variant chr4-15601403-CCTCT-C is described in Lovd as [Pathogenic]. Variant chr4-15601403-CCTCT-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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CC2D2A | NM_001378615.1 | c.4844_4847del | p.Ser1615LeufsTer16 | frameshift_variant | 37/37 | ENST00000424120.6 | |
CC2D2A | NM_001080522.2 | c.4844_4847del | p.Ser1615LeufsTer16 | frameshift_variant | 38/38 | ||
CC2D2A | NM_001378617.1 | c.4697_4700del | p.Ser1566LeufsTer16 | frameshift_variant | 35/35 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CC2D2A | ENST00000424120.6 | c.4844_4847del | p.Ser1615LeufsTer16 | frameshift_variant | 37/37 | 5 | NM_001378615.1 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152154Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000499 AC: 1AN: 200572Hom.: 0 AF XY: 0.00000922 AC XY: 1AN XY: 108472
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GnomAD4 exome AF: 0.0000101 AC: 14AN: 1391750Hom.: 0 AF XY: 0.0000117 AC XY: 8AN XY: 685066
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152154Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74338
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2021 | - - |
Joubert syndrome 9 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
CC2D2A-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 29, 2023 | The CC2D2A c.4844_4847delCTCT variant is predicted to result in a frameshift and premature protein termination (p.Ser1615Leufs*16). This variant has been reported along with a splicing variant in CC2D2A in an individual with Joubert syndrome (Bachmann-Gagescu et al. 2012. PubMed ID: 22241855). Additionally, here at PreventionGenetics, this variant was observed in trans with a pathogenic variant in a patient. This variant is reported in 0.0011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-15603026-CCTCT-C). Frameshift variants in CC2D2A are expected to be pathogenic. Given all the evidence, we interpret this variant as likely pathogenic. - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 20, 2022 | This sequence change results in a frameshift in the CC2D2A gene (p.Ser1615Leufs*16). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the CC2D2A protein and extend the protein by 9 additional amino acid residues. This variant is present in population databases (rs776305976, gnomAD 0.002%). This frameshift has been observed in individual(s) with Joubert syndrome (PMID: 22241855). ClinVar contains an entry for this variant (Variation ID: 217606). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at