rs121912967

Positions:

• chr18-52906134-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_005215.4(DCC):​c.503T>C​(p.Met168Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DCC NM_005215.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.30

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-52906134-T-C is Pathogenic according to our data. Variant chr18-52906134-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 17075.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21370271). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCC	NM_005215.4	c.503T>C	p.Met168Thr	missense_variant	3/29	ENST00000442544.7	NP_005206.2
DCC	XM_017025568.2	c.503T>C	p.Met168Thr	missense_variant	3/29		XP_016881057.1
DCC	XM_017025569.2	c.503T>C	p.Met168Thr	missense_variant	3/29		XP_016881058.1
DCC	XM_047437311.1	c.503T>C	p.Met168Thr	missense_variant	3/29		XP_047293267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCC	ENST00000442544.7	c.503T>C	p.Met168Thr	missense_variant	3/29	1	NM_005215.4	ENSP00000389140	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Esophageal carcinoma, somatic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N;.
MutationTaster	Benign	0.56	D;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.10
Sift	Benign	0.21	T;.
Sift4G	Benign	0.32	T;T
Polyphen		0.0010	B;.
Vest4		0.28
MutPred		0.35		Gain of loop (P = 0.1069);.;
MVP		0.50
MPC		0.22
ClinPred		0.52	D
GERP RS		5.7
Varity_R		0.25
gMVP		0.28

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: rs121912967; hg19: chr18-50432504;