2-37645984-C-T

Variant names:

• chr2-37645984-C-T
• rs201549749
• NM_006449.5:c.604G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006449.5(CDC42EP3):​c.604G>A​(p.Glu202Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000283 in 1,613,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: CDC42EP3 NM_006449.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69
• Publications: 6 publications found

Genes affected

CDC42EP3 (HGNC:16943): (CDC42 effector protein 3) This gene encodes a member of a small family of guanosine triphosphate (GTP) metabolizing proteins that contain a CRIB (Cdc42, Rac interactive binding) domain. Members of this family of proteins act as effectors of CDC42 function. The encoded protein is involved in actin cytoskeleton re-organization during cell shape changes, including pseudopodia formation. A pseudogene of this gene is found on chromosome 19. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

CDC42EP3-AS1 (HGNC:56370): (CDC42EP3 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.069393545).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC42EP3	NM_006449.5	c.604G>A	p.Glu202Lys	missense_variant	Exon 2 of 2	ENST00000295324.4	NP_006440.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC42EP3	ENST00000295324.4	c.604G>A	p.Glu202Lys	missense_variant	Exon 2 of 2	1	NM_006449.5	ENSP00000295324.3

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000187 AC: 47 AN: 250914 AF XY: 0.000207

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000335

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000289 AC: 422 AN: 1461680 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 206 AN XY: 727144

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000201 AC: 9 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53400

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000355 AC: 395 AN: 1111886

Other (OTH) AF: 0.000166 AC: 10 AN: 60388

GnomAD4 genome AF: 0.000224 AC: 34 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74312

African (AFR) AF: 0.0000724 AC: 3 AN: 41414

American (AMR) AF: 0.000262 AC: 4 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68030

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.000492 Hom.: 0

Bravo AF: 0.000272

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000491

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.604G>A (p.E202K) alteration is located in exon 2 (coding exon 1) of the CDC42EP3 gene. This alteration results from a G to A substitution at nucleotide position 604, causing the glutamic acid (E) at amino acid position 202 to be replaced by a lysine (K). 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	0.069
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T;T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.00090
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.73	T;.;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.069	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.
PhyloP100		1.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.75	.;N;N
REVEL	Benign	0.067
Sift	Benign	0.43	.;T;T
Sift4G	Benign	0.63	T;T;.
Polyphen		0.024	B;B;.
Vest4		0.20
MVP		0.47
MPC		0.078
ClinPred		0.027	T
GERP RS		5.9
Varity_R		0.12
gMVP		0.12
Mutation Taster		=88/12	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: rs201549749; hg19: chr2-37873127; COSMIC: COSV54874424; COSMIC: COSV54874424;