NM_005215.4:c.2165-2275T>C

Variant names:

• chr18-53337438-T-C
• rs9950970
• NM_005215.4:c.2165-2275T>C

Variant summary

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

The NM_005215.4(DCC):​c.2165-2275T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 152,158 control chromosomes in the GnomAD database, including 9,982 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 0.34 (9982 hom., cov: 33)
• Consequence: DCC NM_005215.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.173
• Publications: 5 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), Ambry Genetics, Illumina
• 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: Ambry Genetics, G2P
• 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.568 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCC	NM_005215.4	MANE Select	c.2165-2275T>C		intron	N/A	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.2165-2275T>C		intron	N/A	ENSP00000389140.2	P43146
	DCC	ENST00000581580.5	TSL:1	c.1130-2275T>C		intron	N/A	ENSP00000464582.1	J3QS93
	DCC	ENST00000304775.12	TSL:1	n.1964-2275T>C		intron	N/A	ENSP00000304146.8	H0Y2Q5

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51759 AN: 152040 Hom.: 9969 Cov.: 33

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.345

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

GnomAD4 genome AF: 0.340 AC: 51792 AN: 152158 Hom.: 9982 Cov.: 33 AF XY: 0.348 AC XY: 25870 AN XY: 74362

African (AFR) AF: 0.185 AC: 7692 AN: 41552

American (AMR) AF: 0.497 AC: 7603 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1613 AN: 3472

East Asian (EAS) AF: 0.585 AC: 3027 AN: 5174

South Asian (SAS) AF: 0.569 AC: 2744 AN: 4824

European-Finnish (FIN) AF: 0.337 AC: 3562 AN: 10562

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24352 AN: 67968

Other (OTH) AF: 0.348 AC: 736 AN: 2116

Alfa AF: 0.365 Hom.: 13753

Bravo AF: 0.347

Asia WGS AF: 0.535 AC: 1858 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.3
DANN	Benign	0.59
PhyloP100		0.17
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: rs9950970; hg19: chr18-50863808;