22-19479837-G-A

Position:

• chr22-19479837-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001178010.2(CDC45):​c.-132G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 898,450 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (6 hom.)
• Consequence: CDC45 NM_001178010.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.787

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=-0.82).
• BP6: Variant 22-19479837-G-A is Benign according to our data. Variant chr22-19479837-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1201636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00571 (870/152306) while in subpopulation AFR AF= 0.0194 (807/41560). AF 95% confidence interval is 0.0183. There are 15 homozygotes in gnomad4. There are 409 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC45	NM_001178010.2	c.-132G>A		5_prime_UTR_variant	1/20		NP_001171481.1
CDC45	NM_001178011.2	c.-132G>A		5_prime_UTR_variant	1/18		NP_001171482.1
CDC45	XM_011530417.4	c.-132G>A		5_prime_UTR_variant	2/19		XP_011528719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC45	ENST00000437685.6	c.-132G>A		5_prime_UTR_variant	1/20	2		ENSP00000405726
CDC45	ENST00000455750.6	c.-132G>A		5_prime_UTR_variant	2/5	2		ENSP00000413138
CDC45	ENST00000407835.6	c.-454+266G>A		intron_variant		5		ENSP00000385240
CDC45	ENST00000491520.5	n.100G>A		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.00570 AC: 868 AN: 152188 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00813

GnomAD4 exome AF: 0.000776 AC: 579 AN: 746144 Hom.: 6 Cov.: 10 AF XY: 0.000622 AC XY: 245 AN XY: 393722

Gnomad4 AFR exome AF: 0.0217

Gnomad4 AMR exome AF: 0.000977

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000146

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000122

Gnomad4 OTH exome AF: 0.00158

GnomAD4 genome AF: 0.00571 AC: 870 AN: 152306 Hom.: 15 Cov.: 33 AF XY: 0.00549 AC XY: 409 AN XY: 74476

Gnomad4 AFR AF: 0.0194

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00426 Hom.: 1

Bravo AF: 0.00650

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.4
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs114125269; hg19: chr22-19467360;