rs139606873

chr5-55233390-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_021147.5(CCNO):c.134C>A(p.Pro45His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,610,664 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P45P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: CCNO NM_021147.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.27

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0062422752).
• BP6: Variant 5-55233390-G-T is Benign according to our data. Variant chr5-55233390-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 416791.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCNO	NM_021147.5	c.134C>A	p.Pro45His	missense_variant	1/3	ENST00000282572.5
CCNO	NR_125346.2	n.219C>A		non_coding_transcript_exon_variant	1/3
CCNO	NR_125347.2	n.219C>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCNO	ENST00000282572.5	c.134C>A	p.Pro45His	missense_variant	1/3	1	NM_021147.5	P1
CCNO	ENST00000501463.2	c.134C>A	p.Pro45His	missense_variant, NMD_transcript_variant	1/3	1

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 222 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00232

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00144 AC: 344 AN: 238122 Hom.: 0 AF XY: 0.00143 AC XY: 186 AN XY: 130222

Gnomad AFR exome AF: 0.0000678

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000296

Gnomad NFE exome AF: 0.00227

Gnomad OTH exome AF: 0.00223

GnomAD4 exome AF: 0.00133 AC: 1933 AN: 1458366 Hom.: 1 Cov.: 32 AF XY: 0.00128 AC XY: 932 AN XY: 725390

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00245

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000601

Gnomad4 NFE exome AF: 0.00155

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.00128 AC XY: 95 AN XY: 74478

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00232

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00166 Hom.: 0

Bravo AF: 0.00151

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.00199 AC: 17

ExAC AF: 0.00162 AC: 196

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2020

- -

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

- -

Primary ciliary dyskinesia 29 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Mar 20, 2024

BS1, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.071
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.036
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.018	D
Polyphen		0.41	B
Vest4		0.23
MVP		0.63
MPC		0.89
ClinPred		0.032	T
GERP RS		4.3
Varity_R		0.12
gMVP		0.34

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: rs139606873; hg19: chr5-54529218;