rs12958987

Variant names:

• chr18-52832632-G-T
• rs12958987
• NM_005215.4:c.413-73412G>T

Variant summary

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

The NM_005215.4(DCC):​c.413-73412G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 152,060 control chromosomes in the GnomAD database, including 4,544 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 0.22 (4544 hom., cov: 33)
• Consequence: DCC NM_005215.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.155
• Publications: 3 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCC	NM_005215.4	c.413-73412G>T		intron_variant	Intron 2 of 28	ENST00000442544.7	NP_005206.2
DCC	XM_017025568.2	c.413-73412G>T		intron_variant	Intron 2 of 28		XP_016881057.1
DCC	XM_017025569.2	c.413-73412G>T		intron_variant	Intron 2 of 28		XP_016881058.1
DCC	XM_047437311.1	c.413-73412G>T		intron_variant	Intron 2 of 28		XP_047293267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCC	ENST00000442544.7	c.413-73412G>T		intron_variant	Intron 2 of 28	1	NM_005215.4	ENSP00000389140.2

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33709 AN: 151942 Hom.: 4551 Cov.: 33

Gnomad AFR AF: 0.0779

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.340

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.244

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

GnomAD4 genome AF: 0.222 AC: 33696 AN: 152060 Hom.: 4544 Cov.: 33 AF XY: 0.226 AC XY: 16776 AN XY: 74332

African (AFR) AF: 0.0776 AC: 3218 AN: 41456

American (AMR) AF: 0.308 AC: 4705 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 851 AN: 3472

East Asian (EAS) AF: 0.184 AC: 951 AN: 5164

South Asian (SAS) AF: 0.275 AC: 1326 AN: 4820

European-Finnish (FIN) AF: 0.340 AC: 3593 AN: 10574

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 18082 AN: 67996

Other (OTH) AF: 0.244 AC: 516 AN: 2112

Alfa AF: 0.242 Hom.: 845

Bravo AF: 0.216

Asia WGS AF: 0.216 AC: 752 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.37
DANN	Benign	0.32
PhyloP100		-0.15
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: rs12958987; hg19: chr18-50359002;