1-22078579-C-A

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics

ENSG00000289694 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 20 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 3.0373 (below the threshold of 3.09). Trascript score misZ: 2.9016 (below the threshold of 3.09). GenCC associations: The gene is linked to macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome.
• 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 VariationId is 1013509.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001791.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC42	NM_001791.4	MANE Select	c.101C>A	p.Pro34Gln	missense	Exon 2 of 6	NP_001782.1	P60953-2
	CDC42	NM_001039802.2		c.101C>A	p.Pro34Gln	missense	Exon 3 of 7	NP_001034891.1	P60953-2
	CDC42	NM_044472.3		c.101C>A	p.Pro34Gln	missense	Exon 2 of 6	NP_426359.1	P60953-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC42	ENST00000656825.1	MANE Select	c.101C>A	p.Pro34Gln	missense	Exon 2 of 6	ENSP00000499457.1	P60953-2
	CDC42	ENST00000315554.15	TSL:1	c.101C>A	p.Pro34Gln	missense	Exon 2 of 6	ENSP00000314458.8	P60953-1
	CDC42	ENST00000344548.8	TSL:1	c.101C>A	p.Pro34Gln	missense	Exon 3 of 7	ENSP00000341072.3	P60953-2

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

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

African (AFR) AF: 0.0000301 AC: 1 AN: 33220

American (AMR) AF: 0.00 AC: 0 AN: 43908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 84976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106326

Other (OTH) AF: 0.00 AC: 0 AN: 60088

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
1	-	-	CDC42-related disorder (1)
-	1	-	Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.79		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
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

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