rs1057519054

Positions:

• chr18-53386061-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_005215.4(DCC):​c.2378T>G​(p.Val793Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DCC NM_005215.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.77

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain Fibronectin type-III 4 (size 93) in uniprot entity DCC_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_005215.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant 18-53386061-T-G is Pathogenic according to our data. Variant chr18-53386061-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 375282.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-53386061-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCC	NM_005215.4	c.2378T>G	p.Val793Gly	missense_variant	16/29	ENST00000442544.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCC	ENST00000442544.7	c.2378T>G	p.Val793Gly	missense_variant	16/29	1	NM_005215.4	P1
DCC	ENST00000581580.5	c.1343T>G	p.Val448Gly	missense_variant	13/27	1
DCC	ENST00000304775.12	c.2180T>G	p.Val727Gly	missense_variant, NMD_transcript_variant	15/19	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Mirror movements 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 03, 2017

- -

Corpus callosum, agenesis of Pathogenic:1

Pathogenic, no assertion criteria provided

research

Neurogenetics Research; Murdoch Childrens Research Institute

Jan 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T;.;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.28	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.3	D;.;.
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.69
MutPred		0.51		Loss of stability (P = 0.0134);.;.;
MVP		0.91
MPC		0.85
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.97
gMVP		0.70

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: rs1057519054; hg19: chr18-50912431;