rs1554019966
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The NM_021147.5(CCNO):āc.563A>Gā(p.Lys188Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,324 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 (ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
CCNO
NM_021147.5 missense
NM_021147.5 missense
Scores
5
8
6
Clinical Significance
Conservation
PhyloP100: 7.77
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 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.912
PP5
Variant 5-55232365-T-C is Pathogenic according to our data. Variant chr5-55232365-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 525346.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.563A>G | p.Lys188Arg | missense_variant | 2/3 | ENST00000282572.5 | NP_066970.3 | |
CCNO | NR_125346.2 | n.1024A>G | non_coding_transcript_exon_variant | 2/3 | ||||
CCNO | NR_125347.2 | n.653A>G | non_coding_transcript_exon_variant | 2/3 | ||||
CCNO | NR_125348.1 | n.627A>G | non_coding_transcript_exon_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CCNO | ENST00000282572.5 | c.563A>G | p.Lys188Arg | missense_variant | 2/3 | 1 | NM_021147.5 | ENSP00000282572.4 | ||
CCNO | ENST00000501463.2 | n.*543A>G | non_coding_transcript_exon_variant | 2/3 | 1 | ENSP00000422485.1 | ||||
CCNO | ENST00000501463.2 | n.*543A>G | 3_prime_UTR_variant | 2/3 | 1 | ENSP00000422485.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461324Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727000
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1461324
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32
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1
AN XY:
727000
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 24, 2017 | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been found in combination with another pathogenic CCNO variant in a single family affected with primary ciliary dyskinesia (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with arginine at codon 188 of the CCNO protein (p.Lys188Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
H
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Loss of methylation at K188 (P = 0.0087);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -24
Find out detailed SpliceAI scores and Pangolin per-transcript scores at