NM_003504.5:c.464A>G

Variant names:

• chr22-19483983-A-G
• rs9606030
• NM_003504.5:c.464A>G

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.464A>G​(p.Glu155Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,609,416 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: CDC45 NM_003504.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.13
• Publications: 4 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 (MetaRNN=0.0034863353).
• BP6: Variant 22-19483983-A-G is Benign according to our data. Variant chr22-19483983-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1142614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00131 (200/152332) while in subpopulation NFE AF = 0.00143 (97/68032). AF 95% confidence interval is 0.0012. There are 0 homozygotes in GnomAd4. There are 111 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.464A>G	p.Glu155Gly	missense	Exon 5 of 19	NP_003495.1	O75419-1
	CDC45	NM_001178010.2		c.464A>G	p.Glu155Gly	missense	Exon 5 of 20	NP_001171481.1	O75419-3
	CDC45	NM_001369291.1		c.428A>G	p.Glu143Gly	missense	Exon 5 of 19	NP_001356220.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC45	ENST00000263201.7	TSL:1 MANE Select	c.464A>G	p.Glu155Gly	missense	Exon 5 of 19	ENSP00000263201.2	O75419-1
	CDC45	ENST00000437685.6	TSL:2	c.464A>G	p.Glu155Gly	missense	Exon 5 of 20	ENSP00000405726.2	O75419-3
	CDC45	ENST00000932444.1		c.326A>G	p.Glu109Gly	missense	Exon 4 of 18	ENSP00000602503.1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 200 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00631

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00154 AC: 378 AN: 244790 AF XY: 0.00165

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000683

Gnomad ASJ exome AF: 0.00193

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00682

Gnomad NFE exome AF: 0.00160

Gnomad OTH exome AF: 0.000839

GnomAD4 exome AF: 0.00156 AC: 2280 AN: 1457084 Hom.: 3 Cov.: 31 AF XY: 0.00153 AC XY: 1108 AN XY: 724872

African (AFR) AF: 0.000151 AC: 5 AN: 33052

American (AMR) AF: 0.000769 AC: 33 AN: 42922

Ashkenazi Jewish (ASJ) AF: 0.00212 AC: 55 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.000153 AC: 13 AN: 85152

European-Finnish (FIN) AF: 0.00676 AC: 361 AN: 53388

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5750

European-Non Finnish (NFE) AF: 0.00154 AC: 1713 AN: 1111020

Other (OTH) AF: 0.00153 AC: 92 AN: 60182

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74496

African (AFR) AF: 0.000241 AC: 10 AN: 41578

American (AMR) AF: 0.00118 AC: 18 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00631 AC: 67 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.000910

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00152 AC: 184

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000873

EpiControl AF: 0.00178

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	CDC45-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.2	N
PhyloP100		2.1
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.91	N
REVEL	Benign	0.053
Sift	Benign	0.43	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.066
MVP		0.13
MPC		0.37
ClinPred		0.022	T
GERP RS		-0.15
Varity_R		0.032
gMVP		0.15
Mutation Taster		=71/29	polymorphism

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: rs9606030; hg19: chr22-19471506;