Genetic Variant CDC42EP5:p.Ala116Thr (chr19-54465202-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_145057.4(CDC42EP5):c.346G>A(p.Ala116Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000233 in 1,285,424 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: not found (cov: 32)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

CDC42EP5
NM_145057.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.107

Publications

0 publications found

Variant links:

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]

CDC42EP5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09742236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC42EP5	NM_145057.4 link	c.346G>A	p.Ala116Thr	missense_variant	Exon 3 of 3	ENST00000301200.3	NP_659494.2	Q6NZY7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC42EP5	ENST00000301200.3 link	c.346G>A	p.Ala116Thr	missense_variant	Exon 3 of 3	1	NM_145057.4	ENSP00000301200.2		Q6NZY7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000233

AC:

AN:

1285424

Hom.:

Cov.:

AF XY:

0.00000158

AC XY:

AN XY:

632926

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25770

American (AMR)

AF:

0.00

AC:

AN:

20742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21492

East Asian (EAS)

AF:

0.00

AC:

AN:

28086

South Asian (SAS)

AF:

0.0000150

AC:

AN:

66720

European-Finnish (FIN)

AF:

0.0000300

AC:

AN:

33378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4580

European-Non Finnish (NFE)

AF:

9.69e-7

AC:

AN:

1031744

Other (OTH)

AF:

0.00

AC:

AN:

52912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 19, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.346G>A (p.A116T) alteration is located in exon 3 (coding exon 1) of the CDC42EP5 gene. This alteration results from a G to A substitution at nucleotide position 346, causing the alanine (A) at amino acid position 116 to be replaced by a threonine (T). 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

0.079

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.14

M_CAP

Benign

0.032

MetaRNN

Benign

0.097

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PhyloP100

0.11

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.57

REVEL

Benign

0.022

Sift

Benign

0.082

Sift4G

Benign

0.28

Polyphen

0.14

Vest4

0.24

MutPred

0.19

Gain of glycosylation at A116 (P = 0.0017);

MVP

0.30

MPC

0.94

ClinPred

0.11

GERP RS

3.1

Varity_R

0.049

gMVP

0.16

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over