Genetic Variant CDC42EP5:p.Leu93Met (chr19-54465271-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_145057.4(CDC42EP5):c.277C>A(p.Leu93Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000832 in 1,202,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. L93V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

CDC42EP5
NM_145057.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.745

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27379274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC42EP5	NM_145057.4 link	c.277C>A	p.Leu93Met	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.277C>A	p.Leu93Met	missense_variant	Exon 3 of 3	1	NM_145057.4	ENSP00000301200.2		Q6NZY7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.32e-7

AC:

AN:

1202118

Hom.:

Cov.:

AF XY:

0.00000170

AC XY:

AN XY:

586740

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24678

American (AMR)

AF:

0.0000682

AC:

AN:

14670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18830

East Asian (EAS)

AF:

0.00

AC:

AN:

27722

South Asian (SAS)

AF:

0.00

AC:

AN:

50942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29894

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3980

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

983128

Other (OTH)

AF:

0.00

AC:

AN:

48274

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.044

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.44

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.2

PhyloP100

0.74

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-1.1

REVEL

Benign

0.090

Sift

Benign

0.031

Sift4G

Uncertain

0.056

Polyphen

1.0

Vest4

0.19

MutPred

0.31

Loss of stability (P = 0.1165);

MVP

0.34

MPC

2.0

ClinPred

0.93

GERP RS

3.1

Varity_R

0.17

gMVP

0.21

Mutation Taster

=83/17

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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19-54465271-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