5-55233261-TGGGCC-TGGGCCGGGCC

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_021147.5(CCNO):c.258_262dupGGCCC(p.Gln88ArgfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,589,494 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

CCNO
NM_021147.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 0.939

Publications

8 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 links:

CCNO-DT (HGNC:55543): (CCNO divergent transcript)

CCNO-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 5-55233261-T-TGGGCC is Pathogenic according to our data. Variant chr5-55233261-T-TGGGCC is described in ClinVar as [Pathogenic]. Clinvar id is 139600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCNO	NM_021147.5 link	c.258_262dupGGCCC	p.Gln88ArgfsTer8	frameshift_variant	Exon 1 of 3	ENST00000282572.5	NP_066970.3	P22674-1
CCNO	NR_125346.2 link	n.343_347dupGGCCC		non_coding_transcript_exon_variant	Exon 1 of 3
CCNO	NR_125347.2 link	n.343_347dupGGCCC		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CCNO	ENST00000282572.5 link	c.258_262dupGGCCC	p.Gln88ArgfsTer8	frameshift_variant	Exon 1 of 3	1	NM_021147.5	ENSP00000282572.4	P22674-1
CCNO	ENST00000501463.2 link	n.258_262dupGGCCC		non_coding_transcript_exon_variant	Exon 1 of 3	1		ENSP00000422485.1	P22674-2
CCNO-DT	ENST00000749853.1 link	n.184+38_184+42dupCGGGC		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000133

AC:

AN:

202796

AF XY:

0.000108

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000333

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000567

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000125

Gnomad OTH exome

AF:

0.000194

GnomAD4 exome

AF:

0.000106

AC:

153

AN:

1437284

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

713126

show subpopulations

African (AFR)

AF:

0.0000601

AC:

AN:

33260

American (AMR)

AF:

0.0000244

AC:

AN:

40972

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25576

East Asian (EAS)

AF:

0.000257

AC:

AN:

38932

South Asian (SAS)

AF:

0.000120

AC:

AN:

83382

European-Finnish (FIN)

AF:

0.0000421

AC:

AN:

47542

Middle Eastern (MID)

AF:

0.000527

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.000106

AC:

117

AN:

1102412

Other (OTH)

AF:

0.000134

AC:

AN:

59520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000145

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41558

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00117

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67986

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 29

Pathogenic:5

Apr 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frameshift c.258_262dup (p.Gln88ArgfsTer8) variant in CCNO gene has been reported previously in homozygous and compound heterozygous state in individuals affected with primary ciliary dyskinesia (Wallmeier et al. 2014; Casey et al. 2015; Davis et al. 2019). This variant segregated with disease in families consistently with autosomal recessive inheritance (Wallmeier et al. 2014). The p.Gln88ArgfsTer8 variant is reported with an allele frequency of 0.01% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Glutamine 88, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Gln88ArgfsTer8. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Apr 29, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Primary ciliary dyskinesia

Pathogenic:3

Aug 01, 2018

Yale Center for Mendelian Genomics, Yale University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 28, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Gln88ArgfsX8 variant in CCNO has been identified in at least 10 individuals with primary ciliary dyskinesia (PCD; 7 homozygotes, 3 compound heterozygotes) and segregated with disease in 7 affected individuals from 4 families (Wallmeier 2014, Casey 2015, Amirav 2016, Davis 2019). It has also been reported by other clinical laboratories in ClinVar (Variation ID: 139600) and has been identified in 0.06% (10/17424) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the proteinâ€™s amino acid sequence beginning at position 88 and leads to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CCNO gene is an established disease mechanism in autosomal recessive PCD. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive PCD. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong. -

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gln88Argfs*8) in the CCNO gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CCNO are known to be pathogenic (PMID: 24747639). This variant is present in population databases (rs587777502, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 24747639, 24824133, 26777464). ClinVar contains an entry for this variant (Variation ID: 139600). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Jan 05, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20301301, 28199173, 30067075, 28801648, 32622824, 31980526, 34426522, 34569065, 24747639, 24824133, 33577779, 34210339, 34102041, 35804324, 26777464) -

Jan 24, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.94

Mutation Taster

=5/195

disease causing (fs/PTC)

(source)

Splicing

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

Publications

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5-55233261-TGGGCC-TGGGCCGGGCC

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