19-54465150-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_145057.4(CDC42EP5):​c.398G>A​(p.Arg133His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000241 in 1,243,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000024 ( 0 hom. )

Consequence

CDC42EP5
NM_145057.4 missense

Scores

2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.04
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.03598541).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDC42EP5NM_145057.4 linkc.398G>A p.Arg133His 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
CDC42EP5ENST00000301200.3 linkc.398G>A p.Arg133His missense_variant Exon 3 of 3 1 NM_145057.4 ENSP00000301200.2 Q6NZY7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000491
AC:
2
AN:
40704
Hom.:
0
AF XY:
0.0000420
AC XY:
1
AN XY:
23832
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000384
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000430
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000241
AC:
3
AN:
1243998
Hom.:
0
Cov.:
31
AF XY:
0.00000329
AC XY:
2
AN XY:
608772
show subpopulations
Gnomad4 AFR exome
AF:
0.0000407
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000197
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 17, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.398G>A (p.R133H) 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 398, causing the arginine (R) at amino acid position 133 to be replaced by a histidine (H). 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
0.071
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.77
CADD
Benign
13
DANN
Uncertain
0.98
DEOGEN2
Benign
0.013
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.056
N
M_CAP
Benign
0.0054
T
MetaRNN
Benign
0.036
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.26
N
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.17
N
REVEL
Benign
0.024
Sift
Benign
0.34
T
Sift4G
Benign
0.20
T
Polyphen
0.0010
B
Vest4
0.062
MutPred
0.20
Gain of glycosylation at P129 (P = 0.1507);
MVP
0.19
MPC
1.1
ClinPred
0.032
T
GERP RS
-2.1
Varity_R
0.060
gMVP
0.12

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1176654212; hg19: chr19-54976334; API