rs746811253

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_021147.5(CCNO):c.788G>C(p.Arg263Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,443,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

CCNO
NM_021147.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.324

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3854547).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CCNO	NM_021147.5 linkuse as main transcript	c.788G>C	p.Arg263Pro	missense_variant	3/3	ENST00000282572.5	NP_066970.3
CCNO	NR_125346.2 linkuse as main transcript	n.1249G>C		non_coding_transcript_exon_variant	3/3
CCNO	NR_125347.2 linkuse as main transcript	n.878G>C		non_coding_transcript_exon_variant	3/3
CCNO	NR_125348.1 linkuse as main transcript	n.852G>C		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCNO	ENST00000282572.5 linkuse as main transcript	c.788G>C	p.Arg263Pro	missense_variant	3/3	1	NM_021147.5	ENSP00000282572	P1	P22674-1
CCNO	ENST00000501463.2 linkuse as main transcript	c.*768G>C		3_prime_UTR_variant, NMD_transcript_variant	3/3	1		ENSP00000422485		P22674-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000142

AC:

AN:

210808

Hom.:

AF XY:

0.00000871

AC XY:

AN XY:

114820

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000193

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000277

AC:

AN:

1443712

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

716996

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000775

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.06e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000830

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 07, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CCNO protein function. ClinVar contains an entry for this variant (Variation ID: 411598). This missense change has been observed in individual(s) with clinical features of primary ciliary dyskinesia (Invitae). This variant is present in population databases (rs746811253, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 263 of the CCNO protein (p.Arg263Pro). -

CCNO-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2023

The CCNO c.788G>C variant is predicted to result in the amino acid substitution p.Arg263Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.019% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-54527468-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.51

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.74

M_CAP

Benign

0.046

MetaRNN

Benign

0.39

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

1.0

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-4.3

REVEL

Benign

0.15

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0090

Polyphen

0.99

Vest4

0.53

MutPred

0.51

Gain of loop (P = 0.1069);

MVP

0.49

MPC

1.4

ClinPred

0.64

GERP RS

1.3

Varity_R

0.93

gMVP

0.82

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

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