rs587777499

chr5-55233261-T-TGGGCCchr5-55233261-T-TGGGCCGGGCC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_021147.5(CCNO):c.262_263insGGCCC(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:8

Conservation

PhyloP100: 0.939

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

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/exons	MANE
CCNO	NM_021147.5 linkuse as main transcript	c.262_263insGGCCC	p.Gln88ArgfsTer8	frameshift_variant	1/3	ENST00000282572.5
CCNO	NR_125346.2 linkuse as main transcript	n.347_348insGGCCC		non_coding_transcript_exon_variant	1/3
CCNO	NR_125347.2 linkuse as main transcript	n.347_348insGGCCC		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCNO	ENST00000282572.5 linkuse as main transcript	c.262_263insGGCCC	p.Gln88ArgfsTer8	frameshift_variant	1/3	1	NM_021147.5	P1	P22674-1
CCNO	ENST00000501463.2 linkuse as main transcript	c.262_263insGGCCC	p.Gln88ArgfsTer8	frameshift_variant, NMD_transcript_variant	1/3	1			P22674-2

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

GnomAD3 exomes

AF:

0.000133

AC:

AN:

202796

Hom.:

AF XY:

0.000108

AC XY:

AN XY:

110912

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 SAS exome

AF:

0.000184

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

Gnomad4 AFR exome

AF:

0.0000601

Gnomad4 AMR exome

AF:

0.0000244

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000257

Gnomad4 SAS exome

AF:

0.000120

Gnomad4 FIN exome

AF:

0.0000421

Gnomad4 NFE exome

AF:

0.000106

Gnomad4 OTH exome

AF:

0.000134

GnomAD4 genome

AF:

0.000145

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00117

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 29

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 29, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Mar 01, 2023	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. -

Primary ciliary dyskinesia

Pathogenic:3

Likely pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Aug 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 28, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 28, 2023	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:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 26, 2021

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, 24747639, 26777464, 24824133, 32622824, 31980526, 33577779) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over