rs762998472
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001378615.1(CC2D2A):c.1263_1264insGGCATGTTTTGGC(p.Ser422GlyfsTer19) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,252 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
CC2D2A
NM_001378615.1 frameshift
NM_001378615.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.60
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 12 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 4-15527560-T-TGGCATGTTTTGGC is Pathogenic according to our data. Variant chr4-15527560-T-TGGCATGTTTTGGC is described in ClinVar as [Pathogenic]. Clinvar id is 2949355.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CC2D2A | NM_001378615.1 | c.1263_1264insGGCATGTTTTGGC | p.Ser422GlyfsTer19 | frameshift_variant | 12/37 | ENST00000424120.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CC2D2A | ENST00000424120.6 | c.1263_1264insGGCATGTTTTGGC | p.Ser422GlyfsTer19 | frameshift_variant | 12/37 | 5 | NM_001378615.1 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248306Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134638
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461252Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726852
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This premature translational stop signal has been observed in individual(s) with Joubert syndrome (PMID: 31964843). This variant is present in population databases (rs762998472, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ser422Glyfs*19) 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). - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at