NM_001369291.1:c.15+203C>G

Variant names:

• chr22-19479774-C-G
• rs4141528
• NM_001369291.1:c.15+203C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369291.1(CDC45):​c.15+203C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0411 in 656,392 control chromosomes in the GnomAD database, including 1,074 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (293 hom., cov: 33)
  • Exomes 𝑓: 0.039 (781 hom.)
• Consequence: CDC45 NM_001369291.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0860
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 22-19479774-C-G is Benign according to our data. Variant chr22-19479774-C-G is described in ClinVar as Benign. ClinVar VariationId is 1249527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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_001369291.1. 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_001369291.1		c.15+203C>G		intron	N/A	NP_001356220.1
	CDC45	NM_003504.5	MANE Select	c.-195C>G		upstream_gene	N/A	NP_003495.1	O75419-1
	CDC45	NM_001178010.2		c.-195C>G		upstream_gene	N/A	NP_001171481.1	O75419-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC45	ENST00000407835.6	TSL:5	c.-454+203C>G		intron	N/A	ENSP00000385240.2	A0A5K1VW85
	CDC45	ENST00000455750.6	TSL:2	c.-143-52C>G		intron	N/A	ENSP00000413138.2	C9K087
	CDC45	ENST00000491520.5	TSL:5	n.37C>G		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7570 AN: 152084 Hom.: 291 Cov.: 33

Gnomad AFR AF: 0.0840

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0777

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.0959

Gnomad FIN AF: 0.0533

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0373

GnomAD4 exome AF: 0.0385 AC: 19418 AN: 504190 Hom.: 781 Cov.: 6 AF XY: 0.0401 AC XY: 10773 AN XY: 268402

African (AFR) AF: 0.0842 AC: 1172 AN: 13916

American (AMR) AF: 0.101 AC: 2597 AN: 25628

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 256 AN: 15580

East Asian (EAS) AF: 0.111 AC: 3497 AN: 31452

South Asian (SAS) AF: 0.0860 AC: 4506 AN: 52414

European-Finnish (FIN) AF: 0.0408 AC: 1481 AN: 36274

Middle Eastern (MID) AF: 0.00917 AC: 20 AN: 2182

European-Non Finnish (NFE) AF: 0.0164 AC: 4909 AN: 298826

Other (OTH) AF: 0.0351 AC: 980 AN: 27918

GnomAD4 genome AF: 0.0498 AC: 7580 AN: 152202 Hom.: 293 Cov.: 33 AF XY: 0.0532 AC XY: 3962 AN XY: 74406

African (AFR) AF: 0.0840 AC: 3489 AN: 41522

American (AMR) AF: 0.0780 AC: 1193 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3468

East Asian (EAS) AF: 0.117 AC: 605 AN: 5158

South Asian (SAS) AF: 0.0954 AC: 460 AN: 4822

European-Finnish (FIN) AF: 0.0533 AC: 565 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0166 AC: 1132 AN: 68026

Other (OTH) AF: 0.0369 AC: 78 AN: 2114

Alfa AF: 0.0329 Hom.: 18

Bravo AF: 0.0523

Asia WGS AF: 0.107 AC: 372 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.8
DANN	Benign	0.60
PhyloP100		0.086
PromoterAI		0.00040	Neutral
Mutation Taster		=100/0	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: rs4141528; hg19: chr22-19467297;