rs16826536

Positions:

• chr1-22086842-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001791.4(CDC42):​c.462T>C​(p.Tyr154=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0710

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 Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1957 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC42	NM_001791.4	c.462T>C	p.Tyr154=	synonymous_variant	5/6	ENST00000656825.1	NP_001782.1
CDC42	NM_001039802.2	c.462T>C	p.Tyr154=	synonymous_variant	6/7		NP_001034891.1
CDC42	NM_044472.3	c.462T>C	p.Tyr154=	synonymous_variant	5/6		NP_426359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC42	ENST00000656825.1	c.462T>C	p.Tyr154=	synonymous_variant	5/6		NM_001791.4	ENSP00000499457	P3

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1951 AN: 152178 Hom.: 47 Cov.: 32

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

GnomAD3 exomes AF: 0.00478 AC: 1202 AN: 251440 Hom.: 15 AF XY: 0.00394 AC XY: 536 AN XY: 135900

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 SAS exome AF: 0.000751

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.: 37 Cov.: 31 AF XY: 0.00296 AC XY: 2155 AN XY: 727138

Gnomad4 AFR exome AF: 0.0405

Gnomad4 AMR exome AF: 0.00525

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00272

Gnomad4 SAS exome AF: 0.000846

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00224

Gnomad4 OTH exome AF: 0.00462

GnomAD4 genome AF: 0.0129 AC: 1957 AN: 152296 Hom.: 47 Cov.: 32 AF XY: 0.0125 AC XY: 934 AN XY: 74468

Gnomad4 AFR AF: 0.0407

Gnomad4 AMR AF: 0.00738

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00159

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00488 Hom.: 9

Bravo AF: 0.0149

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00166

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.3
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs16826536; hg19: chr1-22413335;