5-55231450-T-C

Position:

• chr5-55231450-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021147.5(CCNO):​c.978A>G​(p.Ile326Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 6.8e-7 (0 hom.)
• Consequence: CCNO NM_021147.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0710

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 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=0.280414).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCNO	NM_021147.5	c.978A>G	p.Ile326Met	missense_variant	3/3	ENST00000282572.5
CCNO	NR_125346.2	n.1439A>G		non_coding_transcript_exon_variant	3/3
CCNO	NR_125347.2	n.1068A>G		non_coding_transcript_exon_variant	3/3
CCNO	NR_125348.1	n.1042A>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCNO	ENST00000282572.5	c.978A>G	p.Ile326Met	missense_variant	3/3	1	NM_021147.5	P1
CCNO	ENST00000501463.2	c.*958A>G		3_prime_UTR_variant, NMD_transcript_variant	3/3	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251372 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135908

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461836 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727228

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 03, 2017

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 sequence change replaces isoleucine with methionine at codon 326 of the CCNO protein (p.Ile326Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 2023

Reported in published literature in brothers with dextro-transposition of the great arteries, who also harbor variants in other genes (Kurtz et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29848184) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.71	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.11
Sift	Benign	0.059	T
Sift4G	Uncertain	0.041	D
Polyphen		0.98	D
Vest4		0.11
MutPred		0.51		Gain of catalytic residue at I326 (P = 0.0161);
MVP		0.61
MPC		0.92
ClinPred		0.74	D
GERP RS		-1.5
Varity_R		0.076
gMVP		0.18

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

Other links and lift over

dbSNP: rs1554019818; hg19: chr5-54527278;