chr5-55231530-GCCGCGAGACCCGCAGCATGCGGT-G
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_021147.5(CCNO):βc.875_897delβ(p.Asp292AlafsTer71) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,554 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β ).
Frequency
Genomes: π 0.000013 ( 0 hom., cov: 33)
Exomes π: 0.0000021 ( 0 hom. )
Consequence
CCNO
NM_021147.5 frameshift
NM_021147.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.49
Genes affected
CCNO (HGNC:18576): (cyclin O) This gene encodes a member of the cyclin protein family, and the encoded protein is involved in regulation of the cell cycle. Disruption of this gene is associated with primary ciliary dyskinesia-19. Alternative splicing results in multiple transcript variants. This gene, which has a previous symbol of UNG2, was erroneously identified as a uracil DNA glycosylase in PubMed ID: 2001396. A later publication, PubMed ID: 8419333, identified this gene's product as a cyclin protein family member. The UNG2 symbol is also used as a specific protein isoform name for the UNG gene (GeneID 7374), so confusion exists in the scientific literature and in some databases for these two genes. [provided by RefSeq, Jul 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.169 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-55231530-GCCGCGAGACCCGCAGCATGCGGT-G is Pathogenic according to our data. Variant chr5-55231530-GCCGCGAGACCCGCAGCATGCGGT-G is described in ClinVar as [Pathogenic]. Clinvar id is 861050.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| CCNO | NM_021147.5 | c.875_897del | p.Asp292AlafsTer71 | frameshift_variant | 3/3 | ENST00000282572.5 | |
| CCNO | NR_125346.2 | n.1336_1358del | non_coding_transcript_exon_variant | 3/3 | |||
| CCNO | NR_125347.2 | n.965_987del | non_coding_transcript_exon_variant | 3/3 | |||
| CCNO | NR_125348.1 | n.939_961del | non_coding_transcript_exon_variant | 2/2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CCNO | ENST00000282572.5 | c.875_897del | p.Asp292AlafsTer71 | frameshift_variant | 3/3 | 1 | NM_021147.5 | P1 | |
| CCNO | ENST00000501463.2 | c.*855_*877del | 3_prime_UTR_variant, NMD_transcript_variant | 3/3 | 1 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152236Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250548Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135700
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461318Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727014
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GnomAD4 genome 0.0000131 AC: 2AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74366
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 23, 2023 | This sequence change creates a premature translational stop signal (p.Asp292Alafs*71) in the CCNO gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 59 amino acid(s) of the CCNO protein. This variant is present in population databases (no rsID available, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CCNO-related conditions. ClinVar contains an entry for this variant (Variation ID: 861050). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the CCNO protein in which other variant(s) (p.Gln321*) have been determined to be pathogenic (PMID: 24747639, 26139845). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at