chr19-54465178-G-A

Variant names:

• chr19-54465178-G-A
• rs746808635
• NM_145057.4:c.370C>T

Variant summary

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

The NM_145057.4(CDC42EP5):​c.370C>T​(p.Arg124Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,422,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CDC42EP5 NM_145057.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.54
• Publications: 0 publications found

Genes affected

CDC42EP5 (HGNC:17408): (CDC42 effector protein 5) Cell division control protein 42 (CDC42), a small Rho GTPase, regulates the formation of F-actin-containing structures through its interaction with the downstream effector proteins. The protein encoded by this gene is a member of the Borg (binder of Rho GTPases) family of CDC42 effector proteins. Borg family proteins contain a CRIB (Cdc42/Rac interactive-binding) domain. They bind to CDC42 and regulate its function negatively. The encoded protein may inhibit c-Jun N-terminal kinase (JNK) independently of CDC42 binding. The protein may also play a role in septin organization and inducing pseudopodia formation in fibroblasts [provided by RefSeq, Jul 2013]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0680415).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC42EP5	NM_145057.4	c.370C>T	p.Arg124Cys	missense_variant	Exon 3 of 3	ENST00000301200.3	NP_659494.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC42EP5	ENST00000301200.3	c.370C>T	p.Arg124Cys	missense_variant	Exon 3 of 3	1	NM_145057.4	ENSP00000301200.2

Frequencies

GnomAD3 genomes AF: 0.0000593 AC: 9 AN: 151862 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000129 AC: 6 AN: 46384 AF XY: 0.000146

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000154

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.000117 AC: 149 AN: 1270602 Hom.: 0 Cov.: 31 AF XY: 0.000115 AC XY: 72 AN XY: 624238

African (AFR) AF: 0.000119 AC: 3 AN: 25302

American (AMR) AF: 0.000177 AC: 3 AN: 16906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19936

East Asian (EAS) AF: 0.00 AC: 0 AN: 28390

South Asian (SAS) AF: 0.00 AC: 0 AN: 63030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33228

Middle Eastern (MID) AF: 0.000857 AC: 4 AN: 4668

European-Non Finnish (NFE) AF: 0.000122 AC: 125 AN: 1026820

Other (OTH) AF: 0.000268 AC: 14 AN: 52322

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 151970 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74290

African (AFR) AF: 0.0000241 AC: 1 AN: 41492

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67898

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.0000634 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.370C>T (p.R124C) alteration is located in exon 3 (coding exon 1) of the CDC42EP5 gene. This alteration results from a C to T substitution at nucleotide position 370, causing the arginine (R) at amino acid position 124 to be replaced by a cysteine (C). 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	0.085
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.2
DANN	Benign	0.97
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-2.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.019
Sift	Benign	0.060	T
Sift4G	Benign	0.18	T
Polyphen		0.56	P
Vest4		0.091
MVP		0.31
MPC		1.2
ClinPred		0.040	T
GERP RS		-1.7
Varity_R		0.052
gMVP		0.14
Mutation Taster		=98/2	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: rs746808635; hg19: chr19-54976362;