18-52752333-C-T

Variant names:

• chr18-52752333-C-T
• rs2037008530
• NM_005215.4:c.371C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005215.4(DCC):​c.371C>T​(p.Ser124Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: DCC NM_005215.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.75

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15483007).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCC	NM_005215.4	c.371C>T	p.Ser124Phe	missense_variant	Exon 2 of 29	ENST00000442544.7	NP_005206.2
DCC	XM_017025568.2	c.371C>T	p.Ser124Phe	missense_variant	Exon 2 of 29		XP_016881057.1
DCC	XM_017025569.2	c.371C>T	p.Ser124Phe	missense_variant	Exon 2 of 29		XP_016881058.1
DCC	XM_047437311.1	c.371C>T	p.Ser124Phe	missense_variant	Exon 2 of 29		XP_047293267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCC	ENST00000442544.7	c.371C>T	p.Ser124Phe	missense_variant	Exon 2 of 29	1	NM_005215.4	ENSP00000389140.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Colorectal cancer Uncertain:1

Jun 09, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.055	T;.;T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.00020
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.26	N;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.43	N;.;.
REVEL	Benign	0.084
Sift	Uncertain	0.014	D;.;.
Sift4G	Uncertain	0.0080	D;D;T
Polyphen		0.018	B;.;.
Vest4		0.32
MutPred		0.37		Loss of disorder (P = 0.001);.;.;
MVP		0.48
MPC		0.20
ClinPred		0.84	D
GERP RS		4.1
Varity_R		0.079
gMVP		0.26

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: rs2037008530; hg19: chr18-50278703;