18-52906065-A-G

Position:

• chr18-52906065-A-G

Variant summary

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

The NM_005215.4(DCC):​c.434A>G​(p.Gln145Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DCC NM_005215.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.97

Genes affected

DCC (HGNC:2701): (DCC netrin 1 receptor) This gene encodes a netrin 1 receptor. The transmembrane protein is a member of the immunoglobulin superfamily of cell adhesion molecules, and mediates axon guidance of neuronal growth cones towards sources of netrin 1 ligand. The cytoplasmic tail interacts with the tyrosine kinases Src and focal adhesion kinase (FAK, also known as PTK2) to mediate axon attraction. The protein partially localizes to lipid rafts, and induces apoptosis in the absence of ligand. The protein functions as a tumor suppressor, and is frequently mutated or downregulated in colorectal cancer and esophageal carcinoma. [provided by RefSeq, Oct 2009]

DCC (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
DCC	NM_005215.4	c.434A>G	p.Gln145Arg	missense_variant	3/29	ENST00000442544.7	NP_005206.2
DCC	XM_017025568.2	c.434A>G	p.Gln145Arg	missense_variant	3/29		XP_016881057.1
DCC	XM_017025569.2	c.434A>G	p.Gln145Arg	missense_variant	3/29		XP_016881058.1
DCC	XM_047437311.1	c.434A>G	p.Gln145Arg	missense_variant	3/29		XP_047293267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCC	ENST00000442544.7	c.434A>G	p.Gln145Arg	missense_variant	3/29	1	NM_005215.4	ENSP00000389140.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2024

The c.434A>G (p.Q145R) alteration is located in exon 3 (coding exon 3) of the DCC gene. This alteration results from a A to G substitution at nucleotide position 434, causing the glutamine (Q) at amino acid position 145 to be replaced by an arginine (R). 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	0.16
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.35	T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.56	N;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	D;.
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.043	D;D
Polyphen		0.46	P;.
Vest4		0.36
MutPred		0.61		Gain of MoRF binding (P = 0.0504);.;
MVP		0.79
MPC		0.21
ClinPred		0.91	D
GERP RS		5.7
Varity_R		0.58
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-50432435;