chr22-19479939-G-T

Position:

• chr22-19479939-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003504.5(CDC45):​c.-30G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0554 in 1,611,828 control chromosomes in the GnomAD database, including 2,749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (227 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2522 hom.)
• Consequence: CDC45 NM_003504.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.89

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 22-19479939-G-T is Benign according to our data. Variant chr22-19479939-G-T is described in ClinVar as [Benign]. Clinvar id is 1252951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC45	NM_003504.5	c.-30G>T		5_prime_UTR_variant	1/19	ENST00000263201.7	NP_003495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC45	ENST00000263201.7	c.-30G>T		5_prime_UTR_variant	1/19	1	NM_003504.5	ENSP00000263201	P1

Frequencies

GnomAD3 genomes AF: 0.0483 AC: 7345 AN: 152180 Hom.: 226 Cov.: 33

Gnomad AFR AF: 0.0247

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0779

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.0414

Gnomad SAS AF: 0.0300

Gnomad FIN AF: 0.0402

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0581

Gnomad OTH AF: 0.0641

GnomAD3 exomes AF: 0.0562 AC: 13891 AN: 247054 Hom.: 484 AF XY: 0.0543 AC XY: 7327 AN XY: 134830

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.0583

Gnomad EAS exome AF: 0.0436

Gnomad SAS exome AF: 0.0351

Gnomad FIN exome AF: 0.0404

Gnomad NFE exome AF: 0.0571

Gnomad OTH exome AF: 0.0628

GnomAD4 exome AF: 0.0561 AC: 81933 AN: 1459530 Hom.: 2522 Cov.: 32 AF XY: 0.0557 AC XY: 40435 AN XY: 726094

Gnomad4 AFR exome AF: 0.0240

Gnomad4 AMR exome AF: 0.0950

Gnomad4 ASJ exome AF: 0.0588

Gnomad4 EAS exome AF: 0.0562

Gnomad4 SAS exome AF: 0.0355

Gnomad4 FIN exome AF: 0.0403

Gnomad4 NFE exome AF: 0.0578

Gnomad4 OTH exome AF: 0.0534

GnomAD4 genome AF: 0.0483 AC: 7362 AN: 152298 Hom.: 227 Cov.: 33 AF XY: 0.0482 AC XY: 3591 AN XY: 74482

Gnomad4 AFR AF: 0.0248

Gnomad4 AMR AF: 0.0782

Gnomad4 ASJ AF: 0.0588

Gnomad4 EAS AF: 0.0415

Gnomad4 SAS AF: 0.0305

Gnomad4 FIN AF: 0.0402

Gnomad4 NFE AF: 0.0581

Gnomad4 OTH AF: 0.0639

Alfa AF: 0.0555 Hom.: 69

Bravo AF: 0.0511

Asia WGS AF: 0.0440 AC: 153 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.7
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs13447182; hg19: chr22-19467462;