chr1-227016972-C-T

Variant names:

• chr1-227016972-C-T
• rs201852267
• NM_001394014.1:c.4694G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001394014.1(CDC42BPA):​c.4694G>A​(p.Arg1565His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000899 in 1,613,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1565C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: CDC42BPA NM_001394014.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.09
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18165472).
• BS2: High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC42BPA	NM_001394014.1	c.4694G>A	p.Arg1565His	missense_variant	Exon 33 of 37	ENST00000366766.8	NP_001380943.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC42BPA	ENST00000366766.8	c.4694G>A	p.Arg1565His	missense_variant	Exon 33 of 37	5	NM_001394014.1	ENSP00000355728.5

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000160 AC: 40 AN: 250552 AF XY: 0.000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000497

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000808 AC: 118 AN: 1460916 Hom.: 0 Cov.: 30 AF XY: 0.0000812 AC XY: 59 AN XY: 726716

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.000493 AC: 22 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.000766 AC: 20 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1111506

Other (OTH) AF: 0.000199 AC: 12 AN: 60360

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74314

African (AFR) AF: 0.0000241 AC: 1 AN: 41422

American (AMR) AF: 0.000785 AC: 12 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68014

Other (OTH) AF: 0.00144 AC: 3 AN: 2090

Alfa AF: 0.000129 Hom.: 0

Bravo AF: 0.000355

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4589G>A (p.R1530H) alteration is located in exon 32 (coding exon 32) of the CDC42BPA gene. This alteration results from a G to A substitution at nucleotide position 4589, causing the arginine (R) at amino acid position 1530 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;T;.;.;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Uncertain	-0.033	T
MutationAssessor	Uncertain	2.1	.;M;.;.;.
PhyloP100		3.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.3	D;.;D;.;.
REVEL	Uncertain	0.37
Sift	Benign	0.053	T;.;T;.;.
Sift4G	Benign	0.089	T;T;T;T;T
Polyphen		1.0	D;.;D;.;.
Vest4		0.42
MVP		0.58
MPC		0.77
ClinPred		0.35	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.70
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201852267; hg19: chr1-227204673; COSMIC: COSV62004345;