NM_003504.5:c.112-105C>T

Variant names:

• chr22-19480848-C-T
• rs13447188
• NM_003504.5:c.112-105C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003504.5(CDC45):​c.112-105C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 676,820 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (10 hom.)
• Consequence: CDC45 NM_003504.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.245
• Publications: 0 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 22-19480848-C-T is Benign according to our data. Variant chr22-19480848-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1214640.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 = 0.00748 (1139/152292) while in subpopulation AFR AF = 0.0236 (979/41548). AF 95% confidence interval is 0.0223. There are 14 homozygotes in GnomAd4. There are 548 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003504.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC45	NM_003504.5	MANE Select	c.112-105C>T		intron	N/A	NP_003495.1	O75419-1
	CDC45	NM_001178010.2		c.112-105C>T		intron	N/A	NP_001171481.1	O75419-3
	CDC45	NM_001369291.1		c.76-105C>T		intron	N/A	NP_001356220.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC45	ENST00000263201.7	TSL:1 MANE Select	c.112-105C>T		intron	N/A	ENSP00000263201.2	O75419-1
	CDC45	ENST00000437685.6	TSL:2	c.112-105C>T		intron	N/A	ENSP00000405726.2	O75419-3
	CDC45	ENST00000932444.1		c.112-105C>T		intron	N/A	ENSP00000602503.1

Frequencies

GnomAD3 genomes AF: 0.00749 AC: 1140 AN: 152174 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00718

GnomAD4 exome AF: 0.00166 AC: 873 AN: 524528 Hom.: 10 AF XY: 0.00145 AC XY: 403 AN XY: 277678

African (AFR) AF: 0.0243 AC: 338 AN: 13890

American (AMR) AF: 0.00367 AC: 80 AN: 21816

Ashkenazi Jewish (ASJ) AF: 0.0123 AC: 188 AN: 15312

East Asian (EAS) AF: 0.00 AC: 0 AN: 31516

South Asian (SAS) AF: 0.0000210 AC: 1 AN: 47600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46736

Middle Eastern (MID) AF: 0.00292 AC: 11 AN: 3770

European-Non Finnish (NFE) AF: 0.000494 AC: 156 AN: 315646

Other (OTH) AF: 0.00351 AC: 99 AN: 28242

GnomAD4 genome AF: 0.00748 AC: 1139 AN: 152292 Hom.: 14 Cov.: 32 AF XY: 0.00736 AC XY: 548 AN XY: 74476

African (AFR) AF: 0.0236 AC: 979 AN: 41548

American (AMR) AF: 0.00379 AC: 58 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68026

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00605 Hom.: 1

Bravo AF: 0.00872

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.0
DANN	Benign	0.57
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs13447188; hg19: chr22-19468371;