22-19480194-C-T

Variant names:

• chr22-19480194-C-T
• rs4141527
• NM_003504.5:c.88C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003504.5(CDC45):​c.88C>T​(p.Leu30Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,613,868 control chromosomes in the GnomAD database, including 1,669 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (292 hom., cov: 32)
  • Exomes 𝑓: 0.030 (1377 hom.)
• Consequence: CDC45 NM_003504.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00100

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 22-19480194-C-T is Benign according to our data. Variant chr22-19480194-C-T is described in ClinVar as [Benign]. Clinvar id is 1168874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.001 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC45	NM_003504.5	c.88C>T	p.Leu30Leu	synonymous_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.88C>T	p.Leu30Leu	synonymous_variant	Exon 2 of 19	1	NM_003504.5	ENSP00000263201.2

Frequencies

GnomAD3 genomes AF: 0.0497 AC: 7565 AN: 152094 Hom.: 290 Cov.: 32

Gnomad AFR AF: 0.0840

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0776

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.0967

Gnomad FIN AF: 0.0532

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0369

GnomAD2 exomes AF: 0.0523 AC: 13147 AN: 251358 AF XY: 0.0498

Gnomad AFR exome AF: 0.0840

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.106

Gnomad FIN exome AF: 0.0494

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0352

GnomAD4 exome AF: 0.0297 AC: 43369 AN: 1461656 Hom.: 1377 Cov.: 34 AF XY: 0.0307 AC XY: 22307 AN XY: 727144

Gnomad4 AFR exome AF: 0.0887 AC: 2968 AN: 33472

Gnomad4 AMR exome AF: 0.107 AC: 4787 AN: 44724

Gnomad4 ASJ exome AF: 0.0171 AC: 448 AN: 26126

Gnomad4 EAS exome AF: 0.109 AC: 4320 AN: 39694

Gnomad4 SAS exome AF: 0.0851 AC: 7338 AN: 86254

Gnomad4 FIN exome AF: 0.0425 AC: 2266 AN: 53340

Gnomad4 NFE exome AF: 0.0171 AC: 19003 AN: 1111900

Gnomad4 Remaining exome AF: 0.0357 AC: 2157 AN: 60378

GnomAD4 genome AF: 0.0498 AC: 7576 AN: 152212 Hom.: 292 Cov.: 32 AF XY: 0.0532 AC XY: 3962 AN XY: 74406

Gnomad4 AFR AF: 0.0840 AC: 0.0839594 AN: 0.0839594

Gnomad4 AMR AF: 0.0779 AC: 0.0779391 AN: 0.0779391

Gnomad4 ASJ AF: 0.0153 AC: 0.015265 AN: 0.015265

Gnomad4 EAS AF: 0.117 AC: 0.117442 AN: 0.117442

Gnomad4 SAS AF: 0.0963 AC: 0.0963455 AN: 0.0963455

Gnomad4 FIN AF: 0.0532 AC: 0.0531875 AN: 0.0531875

Gnomad4 NFE AF: 0.0166 AC: 0.0165834 AN: 0.0165834

Gnomad4 OTH AF: 0.0365 AC: 0.0364929 AN: 0.0364929

Alfa AF: 0.0270 Hom.: 96

Bravo AF: 0.0523

Asia WGS AF: 0.107 AC: 370 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	13
DANN	Benign	0.94
Mutation Taster		=95/5	polymorphism (auto)

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: rs4141527; hg19: chr22-19467717; COSMIC: COSV54245723; COSMIC: COSV54245723;