Genetic Variant CDC45:p.Arg7Gly (chr22-19479987-C-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003504.5(CDC45):c.19C>G(p.Arg7Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,613,790 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

CDC45
NM_003504.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.27

Publications

3 publications found

Variant links:

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

CDC45 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012328148).

BP6

Variant 22-19479987-C-G is Benign according to our data. Variant chr22-19479987-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 809317.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00117 (178/152298) while in subpopulation AMR AF = 0.00294 (45/15304). AF 95% confidence interval is 0.00226. There are 0 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDC45	NM_003504.5	MANE Select	c.19C>G	p.Arg7Gly	missense	Exon 1 of 19	NP_003495.1	O75419-1
CDC45	NM_001178010.2		c.19C>G	p.Arg7Gly	missense	Exon 1 of 20	NP_001171481.1	O75419-3
CDC45	NM_001178011.2		c.19C>G	p.Arg7Gly	missense	Exon 1 of 18	NP_001171482.1	O75419-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDC45	ENST00000263201.7	TSL:1 MANE Select	c.19C>G	p.Arg7Gly	missense	Exon 1 of 19	ENSP00000263201.2	O75419-1
CDC45	ENST00000437685.6	TSL:2	c.19C>G	p.Arg7Gly	missense	Exon 1 of 20	ENSP00000405726.2	O75419-3
CDC45	ENST00000932444.1		c.19C>G	p.Arg7Gly	missense	Exon 1 of 18	ENSP00000602503.1

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

179

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00145

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00135

AC:

338

AN:

250298

AF XY:

0.00151

show subpopulations

Gnomad AFR exome

AF:

0.000251

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00170

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00119

AC:

1737

AN:

1461492

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

878

AN XY:

727062

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33478

American (AMR)

AF:

0.00190

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00168

AC:

145

AN:

86252

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

53116

Middle Eastern (MID)

AF:

0.000524

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00127

AC:

1412

AN:

1111984

Other (OTH)

AF:

0.00104

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

187

281

374

468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00117

AC:

178

AN:

152298

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41552

American (AMR)

AF:

0.00294

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00186

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00146

AC:

AN:

68034

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00113

Hom.:

Bravo

AF:

0.00134

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00143

AC:

174

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00231

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.062

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.8

PhyloP100

3.3

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.29

Sift

Uncertain

0.028

Sift4G

Uncertain

0.047

Polyphen

0.88

Vest4

0.84

MVP

0.53

MPC

1.1

ClinPred

0.079

GERP RS

4.3

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.84

gMVP

0.68

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over