22-19481044-A-G

Variant names:

• chr22-19481044-A-G
• rs879255633
• NM_003504.5:c.203A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_003504.5(CDC45):​c.203A>G​(p.Gln68Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Q68Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDC45 NM_003504.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.95
• 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: PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 22-19481044-A-G is Pathogenic according to our data. Variant chr22-19481044-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 253102.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC45	NM_003504.5	MANE Select	c.203A>G	p.Gln68Arg	missense splice_region	Exon 3 of 19	NP_003495.1
	CDC45	NM_001178010.2		c.203A>G	p.Gln68Arg	missense splice_region	Exon 3 of 20	NP_001171481.1
	CDC45	NM_001369291.1		c.167A>G	p.Gln56Arg	missense splice_region	Exon 3 of 19	NP_001356220.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC45	ENST00000263201.7	TSL:1 MANE Select	c.203A>G	p.Gln68Arg	missense splice_region	Exon 3 of 19	ENSP00000263201.2
	CDC45	ENST00000437685.6	TSL:2	c.203A>G	p.Gln68Arg	missense splice_region	Exon 3 of 20	ENSP00000405726.2
	CDC45	ENST00000404724.7	TSL:2	c.203A>G	p.Gln68Arg	missense splice_region	Exon 3 of 18	ENSP00000384978.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448460 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 721214

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33126

American (AMR) AF: 0.00 AC: 0 AN: 44076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 85094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101444

Other (OTH) AF: 0.00 AC: 0 AN: 59952

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Meier-Gorlin syndrome 7 Pathogenic:2

Oct 20, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Likely Pathogenic, 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. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/27374770).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		8.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.82		Loss of sheet (P = 0.0817)
MVP		0.47
MPC		0.55
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.80
gMVP		0.53
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.77		Position offset: 1

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

Other links and lift over

dbSNP: rs879255633; hg19: chr22-19468567;