22-19479774-C-G

Position:

• chr22-19479774-C-G

Variant summary

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

The NM_001369291.1(CDC45):​c.15+203C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0411 in 656,392 control chromosomes in the GnomAD database, including 1,074 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (293 hom., cov: 33)
  • Exomes 𝑓: 0.039 (781 hom.)
• Consequence: CDC45 NM_001369291.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0860

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=-0.79).
• BP6: Variant 22-19479774-C-G is Benign according to our data. Variant chr22-19479774-C-G is described in ClinVar as [Benign]. Clinvar id is 1249527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC45	NM_001369291.1	c.15+203C>G		intron_variant			NP_001356220.1
CDC45	XM_011530416.2	c.15+203C>G		intron_variant			XP_011528718.1
CDC45	XM_011530417.4	c.-143-52C>G		intron_variant			XP_011528719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC45	ENST00000407835.6	c.-454+203C>G		intron_variant		5		ENSP00000385240
CDC45	ENST00000455750.6	c.-143-52C>G		intron_variant		2		ENSP00000413138
CDC45	ENST00000491520.5	n.37C>G		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7570 AN: 152084 Hom.: 291 Cov.: 33

Gnomad AFR AF: 0.0840

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0777

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.0959

Gnomad FIN AF: 0.0533

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0373

GnomAD4 exome AF: 0.0385 AC: 19418 AN: 504190 Hom.: 781 Cov.: 6 AF XY: 0.0401 AC XY: 10773 AN XY: 268402

Gnomad4 AFR exome AF: 0.0842

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.0164

Gnomad4 EAS exome AF: 0.111

Gnomad4 SAS exome AF: 0.0860

Gnomad4 FIN exome AF: 0.0408

Gnomad4 NFE exome AF: 0.0164

Gnomad4 OTH exome AF: 0.0351

GnomAD4 genome AF: 0.0498 AC: 7580 AN: 152202 Hom.: 293 Cov.: 33 AF XY: 0.0532 AC XY: 3962 AN XY: 74406

Gnomad4 AFR AF: 0.0840

Gnomad4 AMR AF: 0.0780

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.0954

Gnomad4 FIN AF: 0.0533

Gnomad4 NFE AF: 0.0166

Gnomad4 OTH AF: 0.0369

Alfa AF: 0.0329 Hom.: 18

Bravo AF: 0.0523

Asia WGS AF: 0.107 AC: 372 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.8
DANN	Benign	0.60

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: rs4141528; hg19: chr22-19467297;