rs778665661

chr22-19518867-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_003504.5(CDC45):c.1660C>T(p.Arg554Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R554P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: CDC45 NM_003504.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 0.905

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.757
• PP5: Variant 22-19518867-C-T is Pathogenic according to our data. Variant chr22-19518867-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 253101.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDC45	NM_003504.5	c.1660C>T	p.Arg554Trp	missense_variant	18/19	ENST00000263201.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC45	ENST00000263201.7	c.1660C>T	p.Arg554Trp	missense_variant	18/19	1	NM_003504.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251472 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135912

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000280 AC: 41 AN: 1461778 Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23 AN XY: 727206

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74342

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000148 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 12, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 586 of the CDC45 protein (p.Arg586Trp). This variant is present in population databases (rs778665661, gnomAD 0.08%). This missense change has been observed in individual(s) with Meier-Gorlin syndrome (PMID: 27374770). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1660C>T (p.Arg554Trp). ClinVar contains an entry for this variant (Variation ID: 253101). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 27374770) -

Meier-Gorlin syndrome 7 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 20, 2016	- -
Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	This variant is interpreted as Uncertain Significance - Insufficient Evidence, for Meier-Gorlin syndrome 7, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.22
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.72	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.8	M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.96
MVP		0.52
MPC		1.0
ClinPred		0.93	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs778665661; hg19: chr22-19506390; COSMIC: COSV54245132; COSMIC: COSV54245132;