22-19480364-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003504.5(CDC45):c.111+147G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0254 in 761,958 control chromosomes in the GnomAD database, including 322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.031 (84 hom., cov: 32)
  • Exomes 𝑓: 0.024 (238 hom.)
• Consequence: CDC45 NM_003504.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.40

Genes affected

CDC45 (HGNC:1739): (cell division cycle 45) 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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 22-19480364-G-A is Benign according to our data. Variant chr22-19480364-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1212170.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDC45	NM_003504.5	c.111+147G>A		intron_variant		ENST00000263201.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC45	ENST00000263201.7	c.111+147G>A		intron_variant		1	NM_003504.5	P1

Frequencies

GnomAD3 genomes AF: 0.0306 AC: 4662 AN: 152166 Hom.: 84 Cov.: 32

Gnomad AFR AF: 0.0479

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.0273

GnomAD4 exome AF: 0.0241 AC: 14712 AN: 609674 Hom.: 238 AF XY: 0.0244 AC XY: 7943 AN XY: 325176

Gnomad4 AFR exome AF: 0.0534

Gnomad4 AMR exome AF: 0.0159

Gnomad4 ASJ exome AF: 0.0374

Gnomad4 EAS exome AF: 0.00187

Gnomad4 SAS exome AF: 0.0251

Gnomad4 FIN exome AF: 0.0146

Gnomad4 NFE exome AF: 0.0254

Gnomad4 OTH exome AF: 0.0277

GnomAD4 genome AF: 0.0307 AC: 4668 AN: 152284 Hom.: 84 Cov.: 32 AF XY: 0.0297 AC XY: 2209 AN XY: 74482

Gnomad4 AFR AF: 0.0479

Gnomad4 AMR AF: 0.0234

Gnomad4 ASJ AF: 0.0360

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.0299

Gnomad4 FIN AF: 0.0137

Gnomad4 NFE AF: 0.0259

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0287 Hom.: 6

Bravo AF: 0.0324

Asia WGS AF: 0.0190 AC: 65 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	7.1
Dann	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs13447184; hg19: chr22-19467887;