18-53377457-A-G

Variant names:

• chr18-53377457-A-G
• rs11082983
• NM_005215.4:c.2360-8586A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005215.4(DCC):​c.2360-8586A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 151,728 control chromosomes in the GnomAD database, including 2,431 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (2431 hom., cov: 31)
• Consequence: DCC NM_005215.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.226
• Publications: 1 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]

DCC Gene-Disease associations (from GenCC):

• mirror movements 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• mirror movements 1 and/or agenesis of the corpus callosum

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• gaze palsy, familial horizontal, with progressive scoliosis, 2

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics
• connective tissue disorder

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• familial congenital mirror movements

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• colorectal cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)
• esophageal cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCC	NM_005215.4	MANE Select	c.2360-8586A>G		intron	N/A	NP_005206.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCC	ENST00000442544.7	TSL:1 MANE Select	c.2360-8586A>G		intron	N/A	ENSP00000389140.2
	DCC	ENST00000581580.5	TSL:1	c.1325-8586A>G		intron	N/A	ENSP00000464582.1
	DCC	ENST00000304775.12	TSL:1	n.2159-8586A>G		intron	N/A	ENSP00000304146.8

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24353 AN: 151608 Hom.: 2426 Cov.: 31

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0771

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.149

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.161 AC: 24371 AN: 151728 Hom.: 2431 Cov.: 31 AF XY: 0.163 AC XY: 12114 AN XY: 74142

African (AFR) AF: 0.272 AC: 11214 AN: 41302

American (AMR) AF: 0.109 AC: 1656 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.0771 AC: 267 AN: 3462

East Asian (EAS) AF: 0.213 AC: 1094 AN: 5148

South Asian (SAS) AF: 0.141 AC: 676 AN: 4792

European-Finnish (FIN) AF: 0.188 AC: 1980 AN: 10524

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 292

European-Non Finnish (NFE) AF: 0.104 AC: 7037 AN: 67968

Other (OTH) AF: 0.150 AC: 316 AN: 2108

Alfa AF: 0.119 Hom.: 668

Bravo AF: 0.159

Asia WGS AF: 0.190 AC: 660 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.8
DANN	Benign	0.60
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11082983; hg19: chr18-50903827;