rs1060503388

chr5-55231653-G-Achr5-55231653-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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]

ACMG classification

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 3 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	UniProt
CCNO	NM_021147.5	c.775C>T	p.Gln259Ter	stop_gained	3/3	ENST00000282572.5
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	Appris	UniProt
CCNO	ENST00000282572.5	c.775C>T	p.Gln259Ter	stop_gained	3/3	1	NM_021147.5	P1
CCNO	ENST00000501463.2	c.*755C>T		3_prime_UTR_variant, NMD_transcript_variant	3/3	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000528 AC: 1 AN: 189264 Hom.: 0 AF XY: 0.00000976 AC XY: 1 AN XY: 102444

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000127

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1430524 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 709286

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.34	N
MutationTaster	Benign	1.0	D
Vest4		0.80
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060503388; hg19: chr5-54527481;