Genetic Variant CDC45:p.Glu155Val (chr22-19483983-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003504.5(CDC45):c.464A>T(p.Glu155Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E155G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CDC45
NM_003504.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.13

Publications

0 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: PanelApp Australia, 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14186788).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC45	NM_003504.5 link	c.464A>T	p.Glu155Val	missense_variant	Exon 5 of 19	ENST00000263201.7	NP_003495.1	O75419-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC45	ENST00000263201.7 link	c.464A>T	p.Glu155Val	missense_variant	Exon 5 of 19	1	NM_003504.5	ENSP00000263201.2		O75419-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457086

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724872

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33052

American (AMR)

AF:

0.00

AC:

AN:

42922

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26000

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111022

Other (OTH)

AF:

0.00

AC:

AN:

60182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

T;.;T;.;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.80

.;T;T;T;T

M_CAP

Benign

0.0078

MetaRNN

Benign

0.14

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;.;N;N;.

PhyloP100

2.1

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.9

N;N;N;N;N

REVEL

Benign

0.028

Sift

Benign

0.25

T;T;T;T;T

Sift4G

Benign

0.17

T;T;T;T;T

Polyphen

0.16

B;.;B;.;.

Vest4

0.24

MutPred

0.33

Loss of solvent accessibility (P = 0.0052);.;Loss of solvent accessibility (P = 0.0052);Loss of solvent accessibility (P = 0.0052);.;

MVP

0.43

MPC

0.37

ClinPred

0.44

GERP RS

-0.15

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.070

gMVP

0.27

Mutation Taster

=68/32

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over