NM_005215.4:c.2T>C

Variant names:

• chr18-52340789-T-C
• NM_005215.4:c.2T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_005215.4(DCC):​c.2T>C​(p.Met1?) variant causes a start lost change. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DCC NM_005215.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.88

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 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 52 codons. Genomic position: 52752116. Lost 0.035 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-52340789-T-C is Pathogenic according to our data. Variant chr18-52340789-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1077125.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-52340789-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCC	NM_005215.4	c.2T>C	p.Met1?	start_lost	Exon 1 of 29	ENST00000442544.7	NP_005206.2
DCC	XM_017025568.2	c.2T>C	p.Met1?	start_lost	Exon 1 of 29		XP_016881057.1
DCC	XM_017025569.2	c.2T>C	p.Met1?	start_lost	Exon 1 of 29		XP_016881058.1
DCC	XM_047437311.1	c.2T>C	p.Met1?	start_lost	Exon 1 of 29		XP_047293267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCC	ENST00000442544.7	c.2T>C	p.Met1?	start_lost	Exon 1 of 29	1	NM_005215.4	ENSP00000389140.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Partial agenesis of the corpus callosum Pathogenic:1

May 12, 2021

Genetics Institute, Tel Aviv Sourasky Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.67	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.28
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.72	P
Vest4		0.84
MutPred		0.57		Loss of stability (P = 0.0794);
MVP		0.94
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.62
gMVP		0.64

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: chr18-49867159;