chr1-227029074-C-T

Variant names:

• chr1-227029074-C-T
• rs1929860
• NM_001394014.1:c.4015G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001394014.1(CDC42BPA):​c.4015G>A​(p.Val1339Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,613,522 control chromosomes in the GnomAD database, including 80,542 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.30 (6898 hom., cov: 33)
  • Exomes 𝑓: 0.31 (73644 hom.)
• Consequence: CDC42BPA NM_001394014.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.262
• Publications: 32 publications found

Genes affected

CDC42BPA (HGNC:1737): (CDC42 binding protein kinase alpha) The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase contains multiple functional domains. Its kinase domain is highly similar to that of the myotonic dystrophy protein kinase (DMPK). This kinase also contains a Rac interactive binding (CRIB) domain, and has been shown to bind CDC42. It may function as a CDC42 downstream effector mediating CDC42 induced peripheral actin formation, and promoting cytoskeletal reorganization. Multiple alternatively spliced transcript variants have been described. [provided by RefSeq, Sep 2018]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029078722).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394014.1. 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
	CDC42BPA	NM_001394014.1	MANE Select	c.4015G>A	p.Val1339Ile	missense	Exon 30 of 37	NP_001380943.1	Q5VT25-2
	CDC42BPA	NM_001387550.1		c.4102G>A	p.Val1368Ile	missense	Exon 32 of 40	NP_001374479.1	A0A0A0MRJ1
	CDC42BPA	NM_001366019.2		c.3949G>A	p.Val1317Ile	missense	Exon 30 of 37	NP_001352948.1	Q5VT25-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC42BPA	ENST00000366766.8	TSL:5 MANE Select	c.4015G>A	p.Val1339Ile	missense	Exon 30 of 37	ENSP00000355728.5	Q5VT25-2
	CDC42BPA	ENST00000366769.7	TSL:1	c.3910G>A	p.Val1304Ile	missense	Exon 29 of 36	ENSP00000355731.3	Q5VT25-5
	CDC42BPA	ENST00000366764.8	TSL:1	c.3850G>A	p.Val1284Ile	missense	Exon 29 of 36	ENSP00000355726.5	A0A0A0MRJ0

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44980 AN: 151996 Hom.: 6893 Cov.: 33

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.297

GnomAD2 exomes AF: 0.323 AC: 81094 AN: 250802 AF XY: 0.318

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.397

Gnomad ASJ exome AF: 0.302

Gnomad EAS exome AF: 0.433

Gnomad FIN exome AF: 0.369

Gnomad NFE exome AF: 0.323

Gnomad OTH exome AF: 0.308

GnomAD4 exome AF: 0.314 AC: 458910 AN: 1461408 Hom.: 73644 Cov.: 42 AF XY: 0.311 AC XY: 225892 AN XY: 727042

African (AFR) AF: 0.219 AC: 7322 AN: 33474

American (AMR) AF: 0.391 AC: 17463 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 7672 AN: 26134

East Asian (EAS) AF: 0.419 AC: 16635 AN: 39694

South Asian (SAS) AF: 0.215 AC: 18510 AN: 86254

European-Finnish (FIN) AF: 0.360 AC: 19116 AN: 53120

Middle Eastern (MID) AF: 0.251 AC: 1445 AN: 5768

European-Non Finnish (NFE) AF: 0.317 AC: 352446 AN: 1111866

Other (OTH) AF: 0.303 AC: 18301 AN: 60388

GnomAD4 genome AF: 0.296 AC: 45006 AN: 152114 Hom.: 6898 Cov.: 33 AF XY: 0.300 AC XY: 22331 AN XY: 74344

African (AFR) AF: 0.214 AC: 8893 AN: 41498

American (AMR) AF: 0.345 AC: 5275 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1027 AN: 3472

East Asian (EAS) AF: 0.426 AC: 2196 AN: 5158

South Asian (SAS) AF: 0.208 AC: 1002 AN: 4824

European-Finnish (FIN) AF: 0.382 AC: 4038 AN: 10560

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21556 AN: 67992

Other (OTH) AF: 0.294 AC: 622 AN: 2116

Alfa AF: 0.309 Hom.: 23391

Bravo AF: 0.294

TwinsUK AF: 0.333 AC: 1234

ALSPAC AF: 0.317 AC: 1223

ESP6500AA AF: 0.218 AC: 962

ESP6500EA AF: 0.315 AC: 2711

ExAC AF: 0.317 AC: 38522

Asia WGS AF: 0.311 AC: 1078 AN: 3478

EpiCase AF: 0.311

EpiControl AF: 0.314

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.30
DEOGEN2	Benign	0.039	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.1	N
PhyloP100		0.26
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.074
MPC		0.19
ClinPred		0.0022	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.026
gMVP		0.099
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1929860; hg19: chr1-227216775; COSMIC: COSV62006080;