22-19479706-T-G

Position:

• chr22-19479706-T-G

Variant summary

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

The NM_001369291.1(CDC45):​c.15+135T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 692,328 control chromosomes in the GnomAD database, including 260 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (69 hom., cov: 33)
  • Exomes 𝑓: 0.023 (191 hom.)
• Consequence: CDC45 NM_001369291.1 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.191

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 22-19479706-T-G is Benign according to our data. Variant chr22-19479706-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 1223417.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 = 0.0274 (4179/152260) while in subpopulation AFR AF= 0.0393 (1632/41538). AF 95% confidence interval is 0.0377. There are 69 homozygotes in gnomad4. There are 1979 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 69 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC45	NM_001369291.1	c.15+135T>G		intron_variant			NP_001356220.1
CDC45	XM_011530416.2	c.15+135T>G		intron_variant			XP_011528718.1
CDC45	XM_011530417.4	c.-143-120T>G		intron_variant			XP_011528719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC45	ENST00000407835.6	c.-454+135T>G		intron_variant		5		ENSP00000385240
CDC45	ENST00000455750.6	c.-143-120T>G		intron_variant		2		ENSP00000413138
CDC45	ENST00000491520.5			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0274 AC: 4170 AN: 152142 Hom.: 68 Cov.: 33

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.0290

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0257

Gnomad OTH AF: 0.0225

GnomAD4 exome AF: 0.0233 AC: 12576 AN: 540068 Hom.: 191 Cov.: 3 AF XY: 0.0237 AC XY: 6896 AN XY: 291416

Gnomad4 AFR exome AF: 0.0436

Gnomad4 AMR exome AF: 0.0138

Gnomad4 ASJ exome AF: 0.0241

Gnomad4 EAS exome AF: 0.00189

Gnomad4 SAS exome AF: 0.0261

Gnomad4 FIN exome AF: 0.0142

Gnomad4 NFE exome AF: 0.0260

Gnomad4 OTH exome AF: 0.0257

GnomAD4 genome AF: 0.0274 AC: 4179 AN: 152260 Hom.: 69 Cov.: 33 AF XY: 0.0266 AC XY: 1979 AN XY: 74440

Gnomad4 AFR AF: 0.0393

Gnomad4 AMR AF: 0.0212

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.0292

Gnomad4 FIN AF: 0.0137

Gnomad4 NFE AF: 0.0257

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.00656 Hom.: 0

Bravo AF: 0.0280

Asia WGS AF: 0.0190 AC: 66 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	clinical testing	GeneDx	Apr 20, 2019	- -
Likely 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	-0.79
CADD	Benign	4.0
DANN	Benign	0.49

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: rs13447180; hg19: chr22-19467229;