Genetic Variant CDC42EP5:p.Leu148Ile (chr19-54465106-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_145057.4(CDC42EP5):c.442C>A(p.Leu148Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000822 in 1,217,006 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L148V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.2e-7 ( 0 hom. )

Consequence

CDC42EP5
NM_145057.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.662

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03373921).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC42EP5	NM_145057.4 link	c.442C>A	p.Leu148Ile	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.442C>A	p.Leu148Ile	missense_variant	Exon 3 of 3	1	NM_145057.4	ENSP00000301200.2		Q6NZY7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000216

AC:

AN:

46334

AF XY:

0.0000381

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

8.22e-7

AC:

AN:

1217006

Hom.:

Cov.:

AF XY:

0.00000169

AC XY:

AN XY:

592926

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24410

American (AMR)

AF:

0.00

AC:

AN:

13174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16404

East Asian (EAS)

AF:

0.00

AC:

AN:

28624

South Asian (SAS)

AF:

0.0000193

AC:

AN:

51768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

995530

Other (OTH)

AF:

0.00

AC:

AN:

49260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000902

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.60

M_CAP

Benign

0.058

MetaRNN

Benign

0.034

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.97

PhyloP100

0.66

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.51

REVEL

Benign

0.040

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.26

Vest4

0.22

MutPred

0.32

Loss of catalytic residue at L148 (P = 0.0696);

MVP

0.22

MPC

2.0

ClinPred

0.28

GERP RS

2.8

Varity_R

0.31

gMVP

0.080

Mutation Taster

=80/20

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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chr19-54465106-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over