rs752245038

Variant names:

• chr22-19480940-ACTCT-A
• rs752245038
• NM_003504.5:c.112-7_112-4delTCTC

Your query was ambiguous. Multiple possible variants found:

• chr22-19480940-ACTCT-A
• chr22-19480940-ACTCT-ACT
• chr22-19480940-ACTCT-ACTCTCT

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003504.5(CDC45):​c.112-7_112-4delTCTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,417,022 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDC45 NM_003504.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC45	NM_003504.5	c.112-7_112-4delTCTC		splice_region_variant, intron_variant	Intron 2 of 18	ENST00000263201.7	NP_003495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC45	ENST00000263201.7	c.112-12_112-9delCTCT		intron_variant	Intron 2 of 18	1	NM_003504.5	ENSP00000263201.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1417022 Hom.: 0 AF XY: 0.00000142 AC XY: 1 AN XY: 706382

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.53		Position offset: -40
DS_AL_spliceai		0.69		Position offset: 13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs752245038; hg19: chr22-19468463;