2-37646253-A-G

Position:

• chr2-37646253-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006449.5(CDC42EP3):​c.335T>C​(p.Ile112Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDC42EP3 NM_006449.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45

Genes affected

CDC42EP3 (HGNC:16943): (CDC42 effector protein 3) This gene encodes a member of a small family of guanosine triphosphate (GTP) metabolizing proteins that contain a CRIB (Cdc42, Rac interactive binding) domain. Members of this family of proteins act as effectors of CDC42 function. The encoded protein is involved in actin cytoskeleton re-organization during cell shape changes, including pseudopodia formation. A pseudogene of this gene is found on chromosome 19. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

CDC42EP3-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC42EP3	NM_006449.5	c.335T>C	p.Ile112Thr	missense_variant	2/2	ENST00000295324.4	NP_006440.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC42EP3	ENST00000295324.4	c.335T>C	p.Ile112Thr	missense_variant	2/2	1	NM_006449.5	ENSP00000295324.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2024

The c.335T>C (p.I112T) alteration is located in exon 2 (coding exon 1) of the CDC42EP3 gene. This alteration results from a T to C substitution at nucleotide position 335, causing the isoleucine (I) at amino acid position 112 to be replaced by a threonine (T). 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	Uncertain	0.34
BayesDel_addAF	Benign	-0.0022	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.6	.;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	.;D;D
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.33
MutPred		0.46		Loss of stability (P = 0.0038);Loss of stability (P = 0.0038);Loss of stability (P = 0.0038);
MVP		0.76
MPC		0.091
ClinPred		0.95	D
GERP RS		5.9
Varity_R		0.41
gMVP		0.57

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: rs1665460728; hg19: chr2-37873396;