NM_001791.4:c.101C>A

Variant names:

• chr1-22078579-C-A
• rs1645575465
• NM_001791.4:c.101C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001791.4(CDC42):​c.101C>A​(p.Pro34Gln) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P34L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDC42 NM_001791.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 7.33

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]

ENSG00000289694 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain Cell division control protein 42 homolog (size 187) in uniprot entity CDC42_HUMAN there are 34 pathogenic changes around while only 0 benign (100%) in NM_001791.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 1-22078579-C-A is Pathogenic according to our data. Variant chr1-22078579-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1013509.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC42	NM_001791.4	c.101C>A	p.Pro34Gln	missense_variant	Exon 2 of 6	ENST00000656825.1	NP_001782.1
CDC42	NM_001039802.2	c.101C>A	p.Pro34Gln	missense_variant	Exon 3 of 7		NP_001034891.1
CDC42	NM_044472.3	c.101C>A	p.Pro34Gln	missense_variant	Exon 2 of 6		NP_426359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC42	ENST00000656825.1	c.101C>A	p.Pro34Gln	missense_variant	Exon 2 of 6		NM_001791.4	ENSP00000499457.1
ENSG00000289694	ENST00000695855.1	c.101C>A	p.Pro34Gln	missense_variant	Exon 2 of 6			ENSP00000512220.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000138 AC: 2 AN: 1453244 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 722566

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Jul 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 34 of the CDC42 protein (p.Pro34Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a developmental disorder and/or pancytopenia and recurrent infections (PMID: 31130284, 33057194, 33672558, 35982159). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1013509). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

CDC42-related disorder Pathogenic:1

Jun 26, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDC42 c.101C>A variant is predicted to result in the amino acid substitution p.Pro34Gln. his variant has been reported as de novo in two patients with pancytopenia (Patient 17-5428 in Table S1 in Monies. 2019. PubMed ID: 31130284; Asiri et al. 2021. PubMed ID: 33672558). Functional analysis of skin fibroblasts isolated from the patient reported in Asiri et al. showed reduced growth and motility (Asiri et al. 2021. PubMed ID: 33672558). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome Uncertain:1

Mar 30, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 supporting, PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	.;D;D;.;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.;.;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.9	.;H;H;H;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.4	.;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D
Polyphen		1.0	.;D;D;D;.
Vest4		0.82, 0.78
MutPred		0.79		Gain of catalytic residue at P34 (P = 0.0393);Gain of catalytic residue at P34 (P = 0.0393);Gain of catalytic residue at P34 (P = 0.0393);Gain of catalytic residue at P34 (P = 0.0393);Gain of catalytic residue at P34 (P = 0.0393);
MVP		0.89
MPC		3.2
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.98

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: rs1645575465; hg19: chr1-22405072; COSMIC: COSV100212550;