rs17837976

Positions:

• chr1-22081719-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ENSG00000289694 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 1167405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-22081719-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC42	NM_001791.4	c.106-3T>C		splice_region_variant, intron_variant		ENST00000656825.1	NP_001782.1
CDC42	NM_001039802.2	c.106-3T>C		splice_region_variant, intron_variant			NP_001034891.1
CDC42	NM_044472.3	c.106-3T>C		splice_region_variant, intron_variant			NP_426359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC42	ENST00000656825.1	c.106-3T>C		splice_region_variant, intron_variant			NM_001791.4	ENSP00000499457.1
ENSG00000289694	ENST00000695855.1	c.106-3T>C		splice_region_variant, intron_variant				ENSP00000512220.1

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

GnomAD3 exomes AF: 0.0155 AC: 3884 AN: 250174 Hom.: 199 AF XY: 0.0122 AC XY: 1650 AN XY: 135212

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 SAS exome AF: 0.000230

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

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.0931

Gnomad4 ASJ exome AF: 0.00177

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000221

Gnomad4 FIN exome AF: 0.00130

Gnomad4 NFE exome AF: 0.00311

Gnomad4 OTH exome AF: 0.00497

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

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.0596

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00451

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00950 Hom.: 36

Bravo AF: 0.0124

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00360

EpiControl AF: 0.00207

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs17837976; hg19: chr1-22408212;