Genetic Variant CDC42:c.106-23G>T (chr1-22081699-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001791.4(CDC42):c.106-23G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,484,692 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0037 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0053 ( 35 hom. )

Consequence

CDC42
NM_001791.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.564

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

CDC42 links:

ENSG00000289694 (HGNC:):

ENSG00000289694 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BS2

High AC in GnomAd4 at 562 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CDC42	NM_001791.4 link	c.106-23G>T	intron_variant	Intron 2 of 5	ENST00000656825.1	NP_001782.1	P60953-2A0A024RAA5
CDC42	NM_001039802.2 link	c.106-23G>T	intron_variant	Intron 3 of 6		NP_001034891.1	P60953-2A0A024RAA5
CDC42	NM_044472.3 link	c.106-23G>T	intron_variant	Intron 2 of 5		NP_426359.1	P60953-1A0A024RAA6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC42	ENST00000656825.1 link	c.106-23G>T		intron_variant	Intron 2 of 5		NM_001791.4	ENSP00000499457.1		P60953-2
ENSG00000289694	ENST00000695856.1 link	c.106-23G>T		intron_variant	Intron 2 of 5			ENSP00000512221.1

Frequencies

GnomAD3 genomes

AF:

0.00369

AC:

561

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00208

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00697

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00382

AC:

953

AN:

249384

AF XY:

0.00392

show subpopulations

Gnomad AFR exome

AF:

0.000924

Gnomad AMR exome

AF:

0.000903

Gnomad ASJ exome

AF:

0.00160

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00278

Gnomad NFE exome

AF:

0.00672

Gnomad OTH exome

AF:

0.00280

GnomAD4 exome

AF:

0.00526

AC:

7015

AN:

1332384

Hom.:

Cov.:

AF XY:

0.00529

AC XY:

3546

AN XY:

669734

show subpopulations

African (AFR)

AF:

0.000582

AC:

AN:

30928

American (AMR)

AF:

0.00111

AC:

AN:

44308

Ashkenazi Jewish (ASJ)

AF:

0.00126

AC:

AN:

25306

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39096

South Asian (SAS)

AF:

0.00187

AC:

156

AN:

83346

European-Finnish (FIN)

AF:

0.00343

AC:

181

AN:

52828

Middle Eastern (MID)

AF:

0.000907

AC:

AN:

5512

European-Non Finnish (NFE)

AF:

0.00640

AC:

6370

AN:

995076

Other (OTH)

AF:

0.00363

AC:

203

AN:

55984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

317

634

951

1268

1585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

222

444

666

888

1110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00369

AC:

562

AN:

152308

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

263

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

41578

American (AMR)

AF:

0.000915

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00124

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00208

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00697

AC:

474

AN:

68026

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00292

Hom.:

Bravo

AF:

0.00342

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.043

(source)

DANN

Benign

0.47

PhyloP100

-0.56

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over