rs1553196096
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_001791.4(CDC42):c.203G>A(p.Arg68Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
CDC42
NM_001791.4 missense
NM_001791.4 missense
Scores
9
3
1
Clinical Significance
Conservation
PhyloP100: 7.92
Genes affected
CDC42 (HGNC:1736): (cell division cycle 42) The protein encoded by this gene is a small GTPase of the Rho-subfamily, which regulates signaling pathways that control diverse cellular functions including cell morphology, migration, endocytosis and cell cycle progression. This protein is highly similar to Saccharomyces cerevisiae Cdc 42, and is able to complement the yeast cdc42-1 mutant. The product of oncogene Dbl was reported to specifically catalyze the dissociation of GDP from this protein. This protein could regulate actin polymerization through its direct binding to Neural Wiskott-Aldrich syndrome protein (N-WASP), which subsequently activates Arp2/3 complex. Alternative splicing of this gene results in multiple transcript variants. Pseudogenes of this gene have been identified on chromosomes 3, 4, 5, 7, 8 and 20. [provided by RefSeq, Apr 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001791.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.887
PP5
?
Variant 1-22086463-G-A is Pathogenic according to our data. Variant chr1-22086463-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 450370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-22086463-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDC42 | NM_001791.4 | c.203G>A | p.Arg68Gln | missense_variant | 4/6 | ENST00000656825.1 | |
CDC42 | NM_001039802.2 | c.203G>A | p.Arg68Gln | missense_variant | 5/7 | ||
CDC42 | NM_044472.3 | c.203G>A | p.Arg68Gln | missense_variant | 4/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDC42 | ENST00000656825.1 | c.203G>A | p.Arg68Gln | missense_variant | 4/6 | NM_001791.4 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 22, 2021 | This missense change has been observed in individual(s) with clinical features of CDC42-related conditions (PMID: 29394990). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 68 of the CDC42 protein (p.Arg68Gln). ClinVar contains an entry for this variant (Variation ID: 450370). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CDC42 function (PMID: 29394990). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 05, 2017 | The R68Q variant in the CDC42 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R68Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R68Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution is within the switch II domain, which is important for Cdc42 binding and interactions, and occurs at a position that is conserved across species (Watson et al., 2016). Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (Y64C, R66G) have been reported in the Human Gene Mutation Database in association with a CDC42-related disorder (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R68Q as a likely pathogenic variant. - |
Pathogenic, criteria provided, single submitter | research | Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital | Nov 01, 2017 | - - |
Abnormal facial shape;C0850715:Abnormality of blood and blood-forming tissues;C1859778:Postnatal growth retardation;C4021753:Abnormality of the immune system;C4022737:Neurodevelopmental abnormality Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 21, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;.;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
Polyphen
0.68, 0.86
.;P;P;P;.
Vest4
0.77, 0.71
MVP
0.93
MPC
2.3
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at