rs869224

Variant names:

• chr18-53451428-A-G
• rs869224
• NM_005215.4:c.3392+766A>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.3392+766A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.486 in 152,020 control chromosomes in the GnomAD database, including 18,966 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 0.49 (18966 hom., cov: 32)
• Consequence: DCC NM_005215.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.715
• Publications: 9 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCC	NM_005215.4	c.3392+766A>G		intron_variant	Intron 23 of 28	ENST00000442544.7	NP_005206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCC	ENST00000442544.7	c.3392+766A>G		intron_variant	Intron 23 of 28	1	NM_005215.4	ENSP00000389140.2
DCC	ENST00000581580.5	c.2297+766A>G		intron_variant	Intron 20 of 26	1		ENSP00000464582.1

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73853 AN: 151902 Hom.: 18954 Cov.: 32

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.480

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.494

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

GnomAD4 genome AF: 0.486 AC: 73875 AN: 152020 Hom.: 18966 Cov.: 32 AF XY: 0.484 AC XY: 35994 AN XY: 74306

African (AFR) AF: 0.365 AC: 15108 AN: 41420

American (AMR) AF: 0.409 AC: 6255 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 1668 AN: 3472

East Asian (EAS) AF: 0.250 AC: 1295 AN: 5174

South Asian (SAS) AF: 0.382 AC: 1841 AN: 4818

European-Finnish (FIN) AF: 0.625 AC: 6596 AN: 10562

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.580 AC: 39394 AN: 67978

Other (OTH) AF: 0.494 AC: 1044 AN: 2114

Alfa AF: 0.540 Hom.: 22723

Bravo AF: 0.460

Asia WGS AF: 0.344 AC: 1195 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.68
PhyloP100		-0.71
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: rs869224; hg19: chr18-50977798;