rs4141527

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr22-19480194-C-T
• chr22-19480194-C-G

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
• Publications: 9 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: 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 VariationId 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.

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.88C>T	p.Leu30Leu	synonymous	Exon 2 of 19	NP_003495.1	O75419-1
	CDC45	NM_001178010.2		c.88C>T	p.Leu30Leu	synonymous	Exon 2 of 20	NP_001171481.1	O75419-3
	CDC45	NM_001369291.1		c.52C>T	p.Leu18Leu	synonymous	Exon 2 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.88C>T	p.Leu30Leu	synonymous	Exon 2 of 19	ENSP00000263201.2	O75419-1
	CDC45	ENST00000407835.6	TSL:5	c.-417C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 19	ENSP00000385240.2	A0A5K1VW85
	CDC45	ENST00000437685.6	TSL:2	c.88C>T	p.Leu30Leu	synonymous	Exon 2 of 20	ENSP00000405726.2	O75419-3

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

African (AFR) AF: 0.0887 AC: 2968 AN: 33472

American (AMR) AF: 0.107 AC: 4787 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 448 AN: 26126

East Asian (EAS) AF: 0.109 AC: 4320 AN: 39694

South Asian (SAS) AF: 0.0851 AC: 7338 AN: 86254

European-Finnish (FIN) AF: 0.0425 AC: 2266 AN: 53340

Middle Eastern (MID) AF: 0.0142 AC: 82 AN: 5768

European-Non Finnish (NFE) AF: 0.0171 AC: 19003 AN: 1111900

Other (OTH) 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

African (AFR) AF: 0.0840 AC: 3487 AN: 41532

American (AMR) AF: 0.0779 AC: 1192 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3472

East Asian (EAS) AF: 0.117 AC: 606 AN: 5160

South Asian (SAS) AF: 0.0963 AC: 464 AN: 4816

European-Finnish (FIN) AF: 0.0532 AC: 564 AN: 10604

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0166 AC: 1128 AN: 68020

Other (OTH) AF: 0.0365 AC: 77 AN: 2110

Alfa AF: 0.0270 Hom.: 96

Bravo AF: 0.0523

Asia WGS AF: 0.107 AC: 370 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	13
DANN	Benign	0.94
PhyloP100		0.0010
PromoterAI		0.067	Neutral
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

Other links and lift over

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