18-53526691-C-T

Variant names:

• chr18-53526691-C-T
• NM_005215.4:c.4186C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005215.4(DCC):​c.4186C>T​(p.Pro1396Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 6.70
• Publications: 0 publications found

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]

LOC124904304 (HGNC:):

LINC01917 (HGNC:52736): (long intergenic non-protein coding RNA 1917)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005215.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCC	NM_005215.4	MANE Select	c.4186C>T	p.Pro1396Ser	missense	Exon 28 of 29	NP_005206.2	P43146

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCC	ENST00000442544.7	TSL:1 MANE Select	c.4186C>T	p.Pro1396Ser	missense	Exon 28 of 29	ENSP00000389140.2	P43146
	DCC	ENST00000581580.5	TSL:1	c.3085C>T	p.Pro1029Ser	missense	Exon 25 of 27	ENSP00000464582.1	J3QS93
	DCC	ENST00000579702.1	TSL:3	n.271C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	26
DANN	Benign	0.95
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.21
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.037	D
Polyphen		0.94	P
Vest4		0.52
MutPred		0.72		Gain of phosphorylation at P1396 (P = 0.0357)
MVP		0.58
MPC		0.70
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.32
gMVP		0.36
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr18-51053061; COSMIC: COSV71431528; COSMIC: COSV71431528;