rs997489

Variant names:

• chr18-52604153-C-T
• rs997489
• NM_005215.4:c.92-147901C>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.92-147901C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 152,094 control chromosomes in the GnomAD database, including 102 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 0.020 (102 hom., cov: 32)
• Consequence: DCC NM_005215.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.05
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0837 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCC	NM_005215.4	c.92-147901C>T		intron_variant	Intron 1 of 28	ENST00000442544.7	NP_005206.2
DCC	XM_017025568.2	c.92-147901C>T		intron_variant	Intron 1 of 28		XP_016881057.1
DCC	XM_017025569.2	c.92-147901C>T		intron_variant	Intron 1 of 28		XP_016881058.1
DCC	XM_047437311.1	c.92-147901C>T		intron_variant	Intron 1 of 28		XP_047293267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCC	ENST00000442544.7	c.92-147901C>T		intron_variant	Intron 1 of 28	1	NM_005215.4	ENSP00000389140.2

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 3012 AN: 151976 Hom.: 100 Cov.: 32

Gnomad AFR AF: 0.00377

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0651

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.0901

Gnomad SAS AF: 0.0397

Gnomad FIN AF: 0.0461

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00929

Gnomad OTH AF: 0.0220

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

GnomAD4 genome AF: 0.0199 AC: 3020 AN: 152094 Hom.: 102 Cov.: 32 AF XY: 0.0227 AC XY: 1688 AN XY: 74328

African (AFR) AF: 0.00376 AC: 156 AN: 41502

American (AMR) AF: 0.0655 AC: 999 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3470

East Asian (EAS) AF: 0.0905 AC: 467 AN: 5162

South Asian (SAS) AF: 0.0400 AC: 192 AN: 4804

European-Finnish (FIN) AF: 0.0461 AC: 488 AN: 10590

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00929 AC: 632 AN: 67994

Other (OTH) AF: 0.0218 AC: 46 AN: 2110

Alfa AF: 0.0127 Hom.: 58

Bravo AF: 0.0230

Asia WGS AF: 0.0510 AC: 175 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.7
DANN	Benign	0.84
PhyloP100		-2.1
Mutation Taster		=99/1	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: rs997489; hg19: chr18-50130523;