CDC45

protein-coding

cell division cycle 45, the group of CMG helicase complex

Gene summary

The protein encoded by this gene was identified by its strong similarity with Saccharomyces cerevisiae Cdc45, an essential protein required to the initiation of DNA replication. Cdc45 is a member of the highly conserved multiprotein complex including Cdc6/Cdc18, the minichromosome maintenance proteins (MCMs) and DNA polymerase, which is important for early steps of DNA replication in eukaryotes. This protein has been shown to interact with MCM7 and DNA polymerase alpha. Studies of the similar gene in Xenopus suggested that this protein play a pivotal role in the loading of DNA polymerase alpha onto chromatin. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

Previous symbols:

CDC45L2
CDC45L

MANE transcript

NM_003504.5

Inheritance

AR, AD

ClinVar variants

P:28U:143B:76

Top phenotype

Meier-Gorlin syndrome 7

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr22:19,479,457-19,520,612

External References & Databases

Ensembl (ENSG00000093009)

Transcript & Mutation Effects

hg38 • Region Span ~41.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Meier-Gorlin syndrome 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014894

Submitter: Labcorp Genetics (formerly Invitae)

Meier-Gorlin syndrome 7DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014894

Submitter: G2P

Meier-Gorlin syndrome 7DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014894

Submitter: ClinGen

The CDC45 gene is located on chromosome 22 at 22q11.21 and encodes cell division cycle 45 protein, a DNA polymerase required for DNA replication initiation. CDC45 was first reported in relation to autosomal recessive Meier-Gorlin syndrome in 2016 (Fenwick et al., PMID: 27374770). Characteristic features for this disorder include craniosynostosis, microtia, short stature, and absent or small patellae. Additional features include microcephaly, Chiari malformation, mild to severe developmental delay, facial dysmorphism, cleft palate, feeding difficulties, anorectal malformations, joint laxity, delayed bone age, genital anomalies, gastro-esophageal reflux, syndactyly, digital clubbing, proptosis, thin eyebrows, ventricular septal defects, and hearing loss. At least 21 variants (including frameshift, stop-gained, intragenic deletion, splice region, and missense variants) have been reported in 14 individuals from four publications (PMID: 27374770; Ting et al., 2019, PMID: 30986546; Knapp et al. 2021, PMID: 33639314; Li et al. 2021, PMID: 34000999) and are included in this curation. The mechanism of pathogenicity is presumed to be loss of function. This gene-disease relationship is also supported by an animal model and biochemical function (Yoshida et al., 2001, PMID: 11416137; Guernsey et al., 2011, PMID: 21358631). In summary, CDC45 is definitively associated with autosomal recessive Meier-Gorlin syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 05Oct2022 (SOP Version 9).

Meier-Gorlin syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016817

Submitter: Orphanet

Clinical Genomic Database (CGD)

Meier-Gorlin syndrome 7AR

Manifestation: Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 27374770

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CDC45 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 277

Inborn genetic diseasesTotal: 84

not specifiedTotal: 24

Meier-Gorlin syndrome 7Total: 22

CDC45-related disorderTotal: 10

MicrocephalyTotal: 1

Androgen resistance syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003504.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	6 clinvar	58 clinvar	4 clinvar	69
missense		8 clinvar	132 clinvar	14 clinvar		154
nonsense	3 clinvar	2 clinvar	1 clinvar			6
start loss			1 clinvar			1
frameshift	8 clinvar	2 clinvar				10
splice donor/acceptor (+/-2bp)		4 clinvar	3 clinvar			7
Total	11	17	143	72	4	247

Highest pathogenic variant AF is 0.00006753351

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003504.5	RefSeq	NP_003495.1	18	MANE Select
ENST00000263201.7	Ensembl	ENSP00000263201.2	18	MANE Select
NM_001178010.2	RefSeq	NP_001171481.1	19	Standard
NM_001178011.2	RefSeq	NP_001171482.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cell cycle - Homo sapiens (human)
Cell Cycle
Mitotic G1-G1-S phases
Retinoblastoma (RB) in Cancer
G1 to S cell cycle control

Biological Process

DNA replication checkpoint
G1/S transition of mitotic cell cycle
regulation of transcription involved in G1/S transition of mitotic cell cycle
double-strand break repair via break-induced replication
DNA replication

Molecular Function

chromatin binding
DNA replication origin binding
single-stranded DNA binding
protein binding
3'-5' DNA helicase activity

Cellular Component

nucleus
nucleoplasm
nuclear pre-replicative complex
cytoplasm
centrosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000437685
Coding exons: 19
Length: 41154
Individuals with no LoFs: 125703
Homozygous LoFs: 0
Heterozygous LoFs: 45
Defined: 125748
p: 0.000179

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.828	315	359	0.877	0.0000210	3991
Missense (PolyPhen)		67	94.977	0.70544		1014
Synonymous	0.729	129	140	0.922	0.00000846	1091
Loss of Function	3.46	14	36.6	0.383	0.00000173	410

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00076	0.00076	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.00026	0.00026	rare
Other	0.00034	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for initiation of chromosomal DNA replication.;

Recessive Scores

pRec: 0.236

Intolerance Scores

RVIS EVS: -0.27
RVIS percentile EVS: 34.82

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.998

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium