22-19479987-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_003504.5(CDC45):c.19C>G(p.Arg7Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,613,790 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: CDC45 NM_003504.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.27

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012328148).
• BP6: Variant 22-19479987-C-G is Benign according to our data. Variant chr22-19479987-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 809317.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00117 (178/152298) while in subpopulation AMR AF= 0.00294 (45/15304). AF 95% confidence interval is 0.00226. There are 0 homozygotes in gnomad4. There are 90 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDC45	NM_003504.5	c.19C>G	p.Arg7Gly	missense_variant	1/19	ENST00000263201.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC45	ENST00000263201.7	c.19C>G	p.Arg7Gly	missense_variant	1/19	1	NM_003504.5	P1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00145

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00135 AC: 338 AN: 250298 Hom.: 1 AF XY: 0.00151 AC XY: 205 AN XY: 135662

Gnomad AFR exome AF: 0.000251

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00203

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00119 AC: 1737 AN: 1461492 Hom.: 2 Cov.: 32 AF XY: 0.00121 AC XY: 878 AN XY: 727062

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00168

Gnomad4 FIN exome AF: 0.000471

Gnomad4 NFE exome AF: 0.00127

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.00121 AC XY: 90 AN XY: 74474

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00146

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.00134

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00143 AC: 174

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00231

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;T;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.67	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.8	M;.;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.2	D;D;D;D;D
REVEL	Benign	0.29
Sift	Uncertain	0.028	D;D;D;D;D
Sift4G	Uncertain	0.047	D;D;D;D;D
Polyphen		0.88	P;.;P;.;.
Vest4		0.84
MVP		0.53
MPC		1.1
ClinPred		0.079	T
GERP RS		4.3
Varity_R		0.84
gMVP		0.68

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

LitVar

Other links and lift over

dbSNP: rs147730653; hg19: chr22-19467510;