rs1548359

Variant names:

• chr22-19515751-G-C
• rs1548359
• NM_003504.5:c.1440+703G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003504.5(CDC45):​c.1440+703G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.842 in 152,252 control chromosomes in the GnomAD database, including 54,357 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.84 (54357 hom., cov: 33)
• Consequence: CDC45 NM_003504.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0120
• Publications: 2 publications found

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]

CDC45 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC45	NM_003504.5	c.1440+703G>C		intron_variant	Intron 15 of 18	ENST00000263201.7	NP_003495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC45	ENST00000263201.7	c.1440+703G>C		intron_variant	Intron 15 of 18	1	NM_003504.5	ENSP00000263201.2

Frequencies

GnomAD3 genomes AF: 0.842 AC: 128054 AN: 152134 Hom.: 54301 Cov.: 33

Gnomad AFR AF: 0.944

Gnomad AMI AF: 0.828

Gnomad AMR AF: 0.855

Gnomad ASJ AF: 0.827

Gnomad EAS AF: 0.856

Gnomad SAS AF: 0.914

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.791

Gnomad OTH AF: 0.838

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.842 AC: 128170 AN: 152252 Hom.: 54357 Cov.: 33 AF XY: 0.839 AC XY: 62474 AN XY: 74428

African (AFR) AF: 0.944 AC: 39240 AN: 41560

American (AMR) AF: 0.855 AC: 13095 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.827 AC: 2871 AN: 3472

East Asian (EAS) AF: 0.856 AC: 4425 AN: 5168

South Asian (SAS) AF: 0.915 AC: 4413 AN: 4824

European-Finnish (FIN) AF: 0.710 AC: 7506 AN: 10574

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.791 AC: 53823 AN: 68024

Other (OTH) AF: 0.840 AC: 1777 AN: 2116

Alfa AF: 0.822 Hom.: 6422

Bravo AF: 0.854

Asia WGS AF: 0.883 AC: 3071 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.0
DANN	Benign	0.69
PhyloP100		-0.012
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1548359; hg19: chr22-19503274;