rs17837976

Variant names:

• chr1-22081719-T-C
• rs17837976
• NM_001791.4:c.106-3T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001791.4(CDC42):​c.106-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00585 in 1,607,138 control chromosomes in the GnomAD database, including 304 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (44 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (260 hom.)
• Consequence: CDC42 NM_001791.4 splice_region, intron
• Scores: Splicing: ADA: 0.001283
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.720
• Publications: 4 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: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000289694 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 1-22081719-T-C is Benign according to our data. Variant chr1-22081719-T-C is described in ClinVar as Benign. ClinVar VariationId is 1167405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0564 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC42	NM_001791.4	MANE Select	c.106-3T>C		splice_region intron	N/A	NP_001782.1
	CDC42	NM_001039802.2		c.106-3T>C		splice_region intron	N/A	NP_001034891.1
	CDC42	NM_044472.3		c.106-3T>C		splice_region intron	N/A	NP_426359.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC42	ENST00000656825.1	MANE Select	c.106-3T>C		splice_region intron	N/A	ENSP00000499457.1
	CDC42	ENST00000315554.15	TSL:1	c.106-3T>C		splice_region intron	N/A	ENSP00000314458.8
	CDC42	ENST00000344548.8	TSL:1	c.106-3T>C		splice_region intron	N/A	ENSP00000341072.3

Frequencies

GnomAD3 genomes AF: 0.00878 AC: 1336 AN: 152244 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0594

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00451

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.0155 AC: 3884 AN: 250174 AF XY: 0.0122

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.0982

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00326

Gnomad OTH exome AF: 0.00986

GnomAD4 exome AF: 0.00554 AC: 8056 AN: 1454776 Hom.: 260 Cov.: 28 AF XY: 0.00512 AC XY: 3709 AN XY: 724252

African (AFR) AF: 0.00114 AC: 38 AN: 33306

American (AMR) AF: 0.0931 AC: 4146 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.00177 AC: 46 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.000221 AC: 19 AN: 85980

European-Finnish (FIN) AF: 0.00130 AC: 69 AN: 53230

Middle Eastern (MID) AF: 0.000523 AC: 3 AN: 5740

European-Non Finnish (NFE) AF: 0.00311 AC: 3436 AN: 1106174

Other (OTH) AF: 0.00497 AC: 299 AN: 60108

GnomAD4 genome AF: 0.00880 AC: 1341 AN: 152362 Hom.: 44 Cov.: 33 AF XY: 0.00927 AC XY: 691 AN XY: 74510

African (AFR) AF: 0.00214 AC: 89 AN: 41596

American (AMR) AF: 0.0596 AC: 912 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00451 AC: 307 AN: 68034

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00942 Hom.: 37

Bravo AF: 0.0124

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00360

EpiControl AF: 0.00207

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.89
PhyloP100		0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.024
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: rs17837976; hg19: chr1-22408212;