rs797044870

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_001791.4(CDC42):c.196A>G(p.Arg66Gly) variant causes a missense change. 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDC42
NM_001791.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 5.80

Variant links:

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]

CDC42 links:

ENSG00000289694 (HGNC:):

ENSG00000289694 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a turn (size 2) in uniprot entity CDC42_HUMAN there are 4 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, 0.916

PP5

Variant 1-22086456-A-G is Pathogenic according to our data. Variant chr1-22086456-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 208668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-22086456-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC42	NM_001791.4 link	c.196A>G	p.Arg66Gly	missense_variant	Exon 4 of 6	ENST00000656825.1	NP_001782.1	P60953-2A0A024RAA5
CDC42	NM_001039802.2 link	c.196A>G	p.Arg66Gly	missense_variant	Exon 5 of 7		NP_001034891.1	P60953-2A0A024RAA5
CDC42	NM_044472.3 link	c.196A>G	p.Arg66Gly	missense_variant	Exon 4 of 6		NP_426359.1	P60953-1A0A024RAA6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC42	ENST00000656825.1 link	c.196A>G	p.Arg66Gly	missense_variant	Exon 4 of 6		NM_001791.4	ENSP00000499457.1		P60953-2
ENSG00000289694	ENST00000695855.1 link	c.196A>G	p.Arg66Gly	missense_variant	Exon 4 of 6			ENSP00000512220.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1447144

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716830

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome

Pathogenic:3

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 06, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 25, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM2, PM6_Strong, PP3 -

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

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Inborn genetic diseases

Pathogenic:1

Jan 04, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Nov 05, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate mild decrease in GAP-stimulated GTP hydrolysis and markedly impaired effector binding (PMID: 29394990, 27513193); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32231661, 30055020, 33547421, 30696065, 27513193, 28991257, 31231135, 35482294, 32368696, 35139179, 37204479, 29394990) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

.;D;D;.;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;.;.;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.92

D;D;D;D;D

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.5

.;M;M;M;.

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.3

.;D;D;D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0060

.;D;D;D;D

Sift4G

Uncertain

0.013

.;D;D;D;D

Polyphen

0.97, 0.99

.;D;D;D;.

Vest4

0.87, 0.80

MVP

0.95

MPC

3.6

ClinPred

0.99

GERP RS

5.4

Varity_R

0.98

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over