22-19480191-G-A

Variant names:

• chr22-19480191-G-A
• NM_003504.5:c.85G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003504.5(CDC45):​c.85G>A​(p.Ala29Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDC45 NM_003504.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.94
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

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.85G>A	p.Ala29Thr	missense	Exon 2 of 19	NP_003495.1	O75419-1
	CDC45	NM_001178010.2		c.85G>A	p.Ala29Thr	missense	Exon 2 of 20	NP_001171481.1	O75419-3
	CDC45	NM_001369291.1		c.49G>A	p.Ala17Thr	missense	Exon 2 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.85G>A	p.Ala29Thr	missense	Exon 2 of 19	ENSP00000263201.2	O75419-1
	CDC45	ENST00000437685.6	TSL:2	c.85G>A	p.Ala29Thr	missense	Exon 2 of 20	ENSP00000405726.2	O75419-3
	CDC45	ENST00000932444.1		c.85G>A	p.Ala29Thr	missense	Exon 2 of 18	ENSP00000602503.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		5.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.90		Gain of methylation at K34 (P = 0.0619)
MVP		0.67
MPC		1.0
ClinPred		0.97	D
GERP RS		6.0
PromoterAI		0.034	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.74
gMVP		0.66
Mutation Taster		=21/79	disease causing

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

hg19: chr22-19467714;