22-19480191-G-A

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC45	NM_003504.5	c.85G>A	p.Ala29Thr	missense_variant	Exon 2 of 19	ENST00000263201.7	NP_003495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC45	ENST00000263201.7	c.85G>A	p.Ala29Thr	missense_variant	Exon 2 of 19	1	NM_003504.5	ENSP00000263201.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.85G>A (p.A29T) alteration is located in exon 2 (coding exon 2) of the CDC45 gene. This alteration results from a G to A substitution at nucleotide position 85, causing the alanine (A) at amino acid position 29 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;.;.;T;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	.;D;D;D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	2.9	M;.;.;M;M;M
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.48
MutPred		0.90		Gain of methylation at K34 (P = 0.0619);.;Gain of methylation at K34 (P = 0.0619);Gain of methylation at K34 (P = 0.0619);Gain of methylation at K34 (P = 0.0619);Gain of methylation at K34 (P = 0.0619);
MVP		0.67
MPC		1.0
ClinPred		0.97	D
GERP RS		6.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.74
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-19467714;