19-54465150-C-T

Variant names:

• chr19-54465150-C-T
• rs1176654212
• NM_145057.4:c.398G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.04

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

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
CDC42EP5	NM_145057.4	c.398G>A	p.Arg133His	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.398G>A	p.Arg133His	missense_variant	Exon 3 of 3	1	NM_145057.4	ENSP00000301200.2

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

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

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

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

Other links and lift over

dbSNP: rs1176654212; hg19: chr19-54976334;