dbSNP rs16826536: CDC42:p.Tyr154Tyr (chr1-22086842-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001791.4(CDC42):c.462T>C(p.Tyr154Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00404 in 1,613,946 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 47 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 37 hom. )

Consequence

CDC42
NM_001791.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0710

Publications

2 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: ClinGen, Ambry Genetics, G2P, 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 1-22086842-T-C is Benign according to our data. Variant chr1-22086842-T-C is described in ClinVar as Benign. ClinVar VariationId is 790477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.071 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0128 (1957/152296) while in subpopulation AFR AF = 0.0407 (1691/41544). AF 95% confidence interval is 0.0391. There are 47 homozygotes in GnomAd4. There are 934 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1957 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDC42	NM_001791.4	MANE Select	c.462T>C	p.Tyr154Tyr	synonymous	Exon 5 of 6	NP_001782.1	P60953-2
CDC42	NM_001039802.2		c.462T>C	p.Tyr154Tyr	synonymous	Exon 6 of 7	NP_001034891.1	P60953-2
CDC42	NM_044472.3		c.462T>C	p.Tyr154Tyr	synonymous	Exon 5 of 6	NP_426359.1	P60953-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDC42	ENST00000656825.1	MANE Select	c.462T>C	p.Tyr154Tyr	synonymous	Exon 5 of 6	ENSP00000499457.1	P60953-2
CDC42	ENST00000315554.15	TSL:1	c.462T>C	p.Tyr154Tyr	synonymous	Exon 5 of 6	ENSP00000314458.8	P60953-1
CDC42	ENST00000344548.8	TSL:1	c.462T>C	p.Tyr154Tyr	synonymous	Exon 6 of 7	ENSP00000341072.3	P60953-2

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1951

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0407

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00739

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00308

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00159

Gnomad OTH

AF:

0.0119

GnomAD2 exomes

AF:

0.00478

AC:

1202

AN:

251440

AF XY:

0.00394

show subpopulations

Gnomad AFR exome

AF:

0.0445

Gnomad AMR exome

AF:

0.00448

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00288

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00193

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00312

AC:

4567

AN:

1461650

Hom.:

Cov.:

AF XY:

0.00296

AC XY:

2155

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.0405

AC:

1355

AN:

33464

American (AMR)

AF:

0.00525

AC:

235

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000268

AC:

AN:

26130

East Asian (EAS)

AF:

0.00272

AC:

108

AN:

39694

South Asian (SAS)

AF:

0.000846

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00224

AC:

2486

AN:

1111808

Other (OTH)

AF:

0.00462

AC:

279

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

236

473

709

946

1182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

130

260

390

520

650

<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:

0.0129

AC:

1957

AN:

152296

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

934

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0407

AC:

1691

AN:

41544

American (AMR)

AF:

0.00738

AC:

113

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00309

AC:

AN:

5184

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00159

AC:

108

AN:

68028

Other (OTH)

AF:

0.0118

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

166

248

331

414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00605

Hom.:

Bravo

AF:

0.0149

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.00207

EpiControl

AF:

0.00166

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

9.3

(source)

DANN

Benign

0.49

PhyloP100

0.071

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over