1-22081706-AT-ATT

Variant names:

• chr1-22081706-A-AT
• rs201214894
• NM_001791.4:c.106-9dupT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001791.4(CDC42):​c.106-9dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00872 in 1,563,968 control chromosomes in the GnomAD database, including 69 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0089 (62 hom.)
• Consequence: CDC42 NM_001791.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.88
• Publications: 1 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: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000289694 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 1-22081706-A-AT is Benign according to our data. Variant chr1-22081706-A-AT is described in ClinVar as Benign. ClinVar VariationId is 1165494.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 1103 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC42	NM_001791.4	MANE Select	c.106-9dupT		splice_region intron	N/A	NP_001782.1	P60953-2
	CDC42	NM_001039802.2		c.106-9dupT		splice_region intron	N/A	NP_001034891.1	P60953-2
	CDC42	NM_044472.3		c.106-9dupT		splice_region intron	N/A	NP_426359.1	P60953-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC42	ENST00000656825.1	MANE Select	c.106-16_106-15insT		intron	N/A	ENSP00000499457.1	P60953-2
	CDC42	ENST00000315554.15	TSL:1	c.106-16_106-15insT		intron	N/A	ENSP00000314458.8	P60953-1
	CDC42	ENST00000344548.8	TSL:1	c.106-16_106-15insT		intron	N/A	ENSP00000341072.3	P60953-2

Frequencies

GnomAD3 genomes AF: 0.00725 AC: 1103 AN: 152082 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00143

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0160

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.00741 AC: 1849 AN: 249480 AF XY: 0.00743

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00270

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00759

GnomAD4 exome AF: 0.00888 AC: 12534 AN: 1411768 Hom.: 62 Cov.: 25 AF XY: 0.00880 AC XY: 6205 AN XY: 705226

African (AFR) AF: 0.00108 AC: 35 AN: 32414

American (AMR) AF: 0.00486 AC: 216 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.00283 AC: 73 AN: 25762

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39468

South Asian (SAS) AF: 0.00524 AC: 446 AN: 85084

European-Finnish (FIN) AF: 0.0125 AC: 664 AN: 53028

Middle Eastern (MID) AF: 0.00265 AC: 15 AN: 5666

European-Non Finnish (NFE) AF: 0.00997 AC: 10641 AN: 1067250

Other (OTH) AF: 0.00754 AC: 442 AN: 58658

GnomAD4 genome AF: 0.00725 AC: 1103 AN: 152200 Hom.: 7 Cov.: 33 AF XY: 0.00759 AC XY: 565 AN XY: 74434

African (AFR) AF: 0.00142 AC: 59 AN: 41516

American (AMR) AF: 0.00634 AC: 97 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4822

European-Finnish (FIN) AF: 0.0160 AC: 170 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0107 AC: 729 AN: 67998

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.0109 Hom.: 2

Bravo AF: 0.00630

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CDC42-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs201214894; hg19: chr1-22408199;