22-19480129-T-C

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.52-29T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 1,613,198 control chromosomes in the GnomAD database, including 265,792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.48 (19666 hom., cov: 32)
  • Exomes 𝑓: 0.58 (246126 hom.)
• Consequence: CDC45 NM_003504.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.411

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=-0.97).
• BP6: Variant 22-19480129-T-C is Benign according to our data. Variant chr22-19480129-T-C is described in ClinVar as [Benign]. Clinvar id is 1234967.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDC45	NM_003504.5	c.52-29T>C		intron_variant		ENST00000263201.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC45	ENST00000263201.7	c.52-29T>C		intron_variant		1	NM_003504.5	P1

Frequencies

GnomAD3 genomes AF: 0.481 AC: 73098 AN: 151968 Hom.: 19650 Cov.: 32

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.553

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.633

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.532

GnomAD3 exomes AF: 0.552 AC: 138530 AN: 251146 Hom.: 39769 AF XY: 0.566 AC XY: 76854 AN XY: 135800

Gnomad AFR exome AF: 0.223

Gnomad AMR exome AF: 0.540

Gnomad ASJ exome AF: 0.671

Gnomad EAS exome AF: 0.427

Gnomad SAS exome AF: 0.653

Gnomad FIN exome AF: 0.518

Gnomad NFE exome AF: 0.589

Gnomad OTH exome AF: 0.586

GnomAD4 exome AF: 0.576 AC: 840944 AN: 1461112 Hom.: 246126 Cov.: 39 AF XY: 0.579 AC XY: 421056 AN XY: 726932

Gnomad4 AFR exome AF: 0.212

Gnomad4 AMR exome AF: 0.539

Gnomad4 ASJ exome AF: 0.666

Gnomad4 EAS exome AF: 0.403

Gnomad4 SAS exome AF: 0.650

Gnomad4 FIN exome AF: 0.526

Gnomad4 NFE exome AF: 0.588

Gnomad4 OTH exome AF: 0.570

GnomAD4 genome AF: 0.481 AC: 73148 AN: 152086 Hom.: 19666 Cov.: 32 AF XY: 0.482 AC XY: 35806 AN XY: 74344

Gnomad4 AFR AF: 0.228

Gnomad4 AMR AF: 0.553

Gnomad4 ASJ AF: 0.681

Gnomad4 EAS AF: 0.422

Gnomad4 SAS AF: 0.634

Gnomad4 FIN AF: 0.517

Gnomad4 NFE AF: 0.593

Gnomad4 OTH AF: 0.539

Alfa AF: 0.551 Hom.: 7884

Bravo AF: 0.468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	2.9
Dann	Benign	0.62
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs5748232; hg19: chr22-19467652; COSMIC: COSV54244208; COSMIC: COSV54244208;