22-19507454-C-T

Variant names:

• chr22-19507454-C-T
• rs146559223
• NM_003504.5:c.893C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3 PP5_Moderate

The NM_003504.5(CDC45):​c.893C>T​(p.Ala298Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000883228: Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/27374770).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A298D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CDC45 NM_003504.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.37
• Publications: 1 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.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000883228: Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/27374770).
• PP5: Variant 22-19507454-C-T is Pathogenic according to our data. Variant chr22-19507454-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 253104.Status of the report is criteria_provided_single_submitter, 1 stars.

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.893C>T	p.Ala298Val	missense	Exon 11 of 19	NP_003495.1	O75419-1
	CDC45	NM_001178010.2		c.989C>T	p.Ala330Val	missense	Exon 12 of 20	NP_001171481.1	O75419-3
	CDC45	NM_001369291.1		c.857C>T	p.Ala286Val	missense	Exon 11 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.893C>T	p.Ala298Val	missense	Exon 11 of 19	ENSP00000263201.2	O75419-1
	CDC45	ENST00000437685.6	TSL:2	c.989C>T	p.Ala330Val	missense	Exon 12 of 20	ENSP00000405726.2	O75419-3
	CDC45	ENST00000932444.1		c.755C>T	p.Ala252Val	missense	Exon 10 of 18	ENSP00000602503.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Meier-Gorlin syndrome 7 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0062	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T
Eigen	Benign	0.029
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0063	T
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		6.4
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.092
Sift	Benign	0.60	T
Sift4G	Benign	0.11	T
Polyphen		0.064	B
Vest4		0.88
MutPred		0.68		Gain of methylation at K301 (P = 0.086)
MVP		0.44
MPC		0.43
ClinPred		0.62	D
GERP RS		4.8
Varity_R		0.18
gMVP		0.38
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs146559223; hg19: chr22-19494977;