rs1060503388
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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):c.775C>T(p.Gln259Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,430,524 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 (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
CCNO
NM_021147.5 stop_gained
NM_021147.5 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 0.669
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 0.264 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-55231653-G-A is Pathogenic according to our data. Variant chr5-55231653-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 411596.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CCNO | NM_021147.5 | c.775C>T | p.Gln259Ter | stop_gained | 3/3 | ENST00000282572.5 | NP_066970.3 | |
| CCNO | NR_125346.2 | n.1236C>T | non_coding_transcript_exon_variant | 3/3 | ||||
| CCNO | NR_125347.2 | n.865C>T | non_coding_transcript_exon_variant | 3/3 | ||||
| CCNO | NR_125348.1 | n.839C>T | non_coding_transcript_exon_variant | 2/2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CCNO | ENST00000282572.5 | c.775C>T | p.Gln259Ter | stop_gained | 3/3 | 1 | NM_021147.5 | ENSP00000282572 | P1 | |
| CCNO | ENST00000501463.2 | c.*755C>T | 3_prime_UTR_variant, NMD_transcript_variant | 3/3 | 1 | ENSP00000422485 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000528 AC: 1AN: 189264Hom.: 0 AF XY: 0.00000976 AC XY: 1AN XY: 102444
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GnomAD4 exome AF: 0.00000140 AC: 2AN: 1430524Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1AN XY: 709286
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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 | Mar 13, 2018 | This sequence change results in a premature translational stop signal in the last exon of the CCNO mRNA at codon 259 (p.Gln259*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 92 amino acids of the CCNO protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CCNO-related disease. This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual with features consistent with primary ciliary dyskineseia (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Experimental studies have not been reported for this truncating variant and it is currently unknown if the last 92 amino acids of the CCNO protein are critical for its function. A different truncation downstream of this variant (p.Gln321X) has been determined to be pathogenic (PMID: 24747639, 26139845). This suggests that deletion of this region of the CCNO protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
MutationTaster
Benign
D
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