1-22078709-T-A

Variant names:

• chr1-22078709-T-A
• rs75284716
• NM_001791.4:c.105+126T>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_001791.4(CDC42):​c.105+126T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,509,282 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0077 (14 hom., cov: 32)
  • Exomes 𝑓: 0.011 (88 hom.)
• Consequence: CDC42 NM_001791.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.22
• 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics

ENSG00000289694 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.119).
• BP6: Variant 1-22078709-T-A is Benign according to our data. Variant chr1-22078709-T-A is described in ClinVar as Benign. ClinVar VariationId is 1694498.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 1174 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.105+126T>A		intron	N/A	NP_001782.1	P60953-2
	CDC42	NM_001039802.2		c.105+126T>A		intron	N/A	NP_001034891.1	P60953-2
	CDC42	NM_044472.3		c.105+126T>A		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.105+126T>A		intron	N/A	ENSP00000499457.1	P60953-2
	CDC42	ENST00000315554.15	TSL:1	c.105+126T>A		intron	N/A	ENSP00000314458.8	P60953-1
	CDC42	ENST00000344548.8	TSL:1	c.105+126T>A		intron	N/A	ENSP00000341072.3	P60953-2

Frequencies

GnomAD3 genomes AF: 0.00772 AC: 1175 AN: 152192 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0193

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00698 AC: 942 AN: 135030 AF XY: 0.00675

Gnomad AFR exome AF: 0.00170

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0181

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00487

GnomAD4 exome AF: 0.0110 AC: 14928 AN: 1356972 Hom.: 88 Cov.: 30 AF XY: 0.0105 AC XY: 7053 AN XY: 668776

African (AFR) AF: 0.00160 AC: 48 AN: 29940

American (AMR) AF: 0.00196 AC: 59 AN: 30160

Ashkenazi Jewish (ASJ) AF: 0.00185 AC: 44 AN: 23800

East Asian (EAS) AF: 0.00 AC: 0 AN: 34432

South Asian (SAS) AF: 0.000796 AC: 60 AN: 75348

European-Finnish (FIN) AF: 0.0173 AC: 717 AN: 41396

Middle Eastern (MID) AF: 0.000544 AC: 3 AN: 5518

European-Non Finnish (NFE) AF: 0.0128 AC: 13541 AN: 1060440

Other (OTH) AF: 0.00815 AC: 456 AN: 55938

GnomAD4 genome AF: 0.00771 AC: 1174 AN: 152310 Hom.: 14 Cov.: 32 AF XY: 0.00777 AC XY: 579 AN XY: 74474

African (AFR) AF: 0.00195 AC: 81 AN: 41558

American (AMR) AF: 0.00242 AC: 37 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0193 AC: 205 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0123 AC: 835 AN: 68034

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00954 Hom.: 5

Bravo AF: 0.00605

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Uncertain	0.98
PhyloP100		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs75284716; hg19: chr1-22405202; COSMIC: COSV104537548;