chr19-54465348-G-T

Variant names:

• chr19-54465348-G-T
• rs1258130123
• NM_145057.4:c.200C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145057.4(CDC42EP5):​c.200C>A​(p.Ala67Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,159,526 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A67G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: CDC42EP5 NM_145057.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.101
• Publications: 1 publications found

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

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=0.13346678).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145057.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC42EP5	NM_145057.4	MANE Select	c.200C>A	p.Ala67Asp	missense	Exon 3 of 3	NP_659494.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC42EP5	ENST00000301200.3	TSL:1 MANE Select	c.200C>A	p.Ala67Asp	missense	Exon 3 of 3	ENSP00000301200.2	Q6NZY7
	CDC42EP5	ENST00000870796.1		c.200C>A	p.Ala67Asp	missense	Exon 2 of 2	ENSP00000540855.1
	CDC42EP5	ENST00000912085.1		c.200C>A	p.Ala67Asp	missense	Exon 2 of 2	ENSP00000582144.1

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 147828 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000301

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000247 AC: 25 AN: 1011698 Hom.: 0 Cov.: 27 AF XY: 0.0000273 AC XY: 13 AN XY: 476498

African (AFR) AF: 0.00 AC: 0 AN: 20254

American (AMR) AF: 0.000160 AC: 1 AN: 6246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11312

East Asian (EAS) AF: 0.00 AC: 0 AN: 20500

South Asian (SAS) AF: 0.00 AC: 0 AN: 18874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2528

European-Non Finnish (NFE) AF: 0.0000274 AC: 24 AN: 874952

Other (OTH) AF: 0.00 AC: 0 AN: 38626

GnomAD4 genome AF: 0.0000135 AC: 2 AN: 147828 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71994

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

African (AFR) AF: 0.00 AC: 0 AN: 40968

American (AMR) AF: 0.00 AC: 0 AN: 14888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000301 AC: 2 AN: 66466

Other (OTH) AF: 0.00 AC: 0 AN: 2040

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.16	N
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.10
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.020
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.019	D
Polyphen		0.46	P
Vest4		0.15
MutPred		0.25		Gain of relative solvent accessibility (P = 0.1066)
MVP		0.20
MPC		1.3
ClinPred		0.40	T
GERP RS		1.2
Varity_R		0.28
gMVP		0.23
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs1258130123; hg19: chr19-54976532;