rs775051461

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP5_Moderate

The NM_021147.5(CCNO):c.638T>C(p.Leu213Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000333 in 1,559,878 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

CCNO
NM_021147.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.06

Publications

7 publications found

Variant links:

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]

CCNO Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 29
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Ambry Genetics
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CCNO links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP5

Variant 5-55231790-A-G is Pathogenic according to our data. Variant chr5-55231790-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 411594.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CCNO	NM_021147.5 link	c.638T>C	p.Leu213Pro	missense_variant	Exon 3 of 3	ENST00000282572.5	NP_066970.3
CCNO	NR_125346.2 link	n.1099T>C		non_coding_transcript_exon_variant	Exon 3 of 3
CCNO	NR_125347.2 link	n.728T>C		non_coding_transcript_exon_variant	Exon 3 of 3
CCNO	NR_125348.1 link	n.702T>C		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CCNO	ENST00000282572.5 link	c.638T>C	p.Leu213Pro	missense_variant	Exon 3 of 3	1	NM_021147.5	ENSP00000282572.4
CCNO	ENST00000501463.2 link	n.*618T>C		non_coding_transcript_exon_variant	Exon 3 of 3	1		ENSP00000422485.1
CCNO	ENST00000501463.2 link	n.*618T>C		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000422485.1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000981

AC:

AN:

163042

AF XY:

0.000149

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000390

Gnomad ASJ exome

AF:

0.00142

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000469

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000305

AC:

AN:

1407622

Hom.:

Cov.:

AF XY:

0.0000417

AC XY:

AN XY:

695118

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32196

American (AMR)

AF:

0.00

AC:

AN:

36834

Ashkenazi Jewish (ASJ)

AF:

0.00103

AC:

AN:

25222

East Asian (EAS)

AF:

0.00

AC:

AN:

36762

South Asian (SAS)

AF:

0.00

AC:

AN:

79946

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48450

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5122

European-Non Finnish (NFE)

AF:

0.00000922

AC:

AN:

1084754

Other (OTH)

AF:

0.000120

AC:

AN:

58336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41476

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000229

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000343

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Pathogenic:1

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 213 of the CCNO protein (p.Leu213Pro). This variant is present in population databases (rs775051461, gnomAD 0.1%). This missense change has been observed in individual(s) with mucociliary clearance disorder (PMID: 26777464). ClinVar contains an entry for this variant (Variation ID: 411594). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CCNO protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CCNO function (PMID: 26777464). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-0.62

MutationAssessor

Pathogenic

3.5

PhyloP100

9.1

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.3

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Vest4

0.97

ClinPred

0.87

GERP RS

5.5

Varity_R

0.95

gMVP

0.89

Mutation Taster

=18/82

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over