chr1-22086456-A-G

Position:

• chr1-22086456-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.80

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a chain Cell division control protein 42 homolog (size 187) in uniprot entity CDC42_HUMAN there are 14 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/exons	MANE	Protein	UniProt
CDC42	NM_001791.4	c.196A>G	p.Arg66Gly	missense_variant	4/6	ENST00000656825.1	NP_001782.1
CDC42	NM_001039802.2	c.196A>G	p.Arg66Gly	missense_variant	5/7		NP_001034891.1
CDC42	NM_044472.3	c.196A>G	p.Arg66Gly	missense_variant	4/6		NP_426359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC42	ENST00000656825.1	c.196A>G	p.Arg66Gly	missense_variant	4/6		NM_001791.4	ENSP00000499457	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1447144 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 06, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 25, 2023	PS4, PM2, PM6_Strong, PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	-	- -

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

-

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2018

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 05, 2023

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	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
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	D
LIST_S2	Uncertain	0.90	D;.;.;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.5	.;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
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	D
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

Other links and lift over

dbSNP: rs797044870; hg19: chr1-22412949;