NM_005215.4:c.91+1496T>C

Variant names:

• chr18-52342374-T-C
• rs4940177
• NM_005215.4:c.91+1496T>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.91+1496T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.849 in 150,996 control chromosomes in the GnomAD database, including 54,390 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 0.85 (54390 hom., cov: 25)
• Consequence: DCC NM_005215.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37
• 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCC	NM_005215.4	c.91+1496T>C		intron_variant	Intron 1 of 28	ENST00000442544.7	NP_005206.2
DCC	XM_017025568.2	c.91+1496T>C		intron_variant	Intron 1 of 28		XP_016881057.1
DCC	XM_017025569.2	c.91+1496T>C		intron_variant	Intron 1 of 28		XP_016881058.1
DCC	XM_047437311.1	c.91+1496T>C		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.91+1496T>C		intron_variant	Intron 1 of 28	1	NM_005215.4	ENSP00000389140.2

Frequencies

GnomAD3 genomes AF: 0.849 AC: 128049 AN: 150882 Hom.: 54347 Cov.: 25

Gnomad AFR AF: 0.880

Gnomad AMI AF: 0.911

Gnomad AMR AF: 0.865

Gnomad ASJ AF: 0.821

Gnomad EAS AF: 0.890

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.786

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.835

Gnomad OTH AF: 0.843

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

GnomAD4 genome AF: 0.849 AC: 128145 AN: 150996 Hom.: 54390 Cov.: 25 AF XY: 0.846 AC XY: 62360 AN XY: 73684

African (AFR) AF: 0.880 AC: 36132 AN: 41068

American (AMR) AF: 0.865 AC: 13160 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.821 AC: 2847 AN: 3466

East Asian (EAS) AF: 0.890 AC: 4483 AN: 5036

South Asian (SAS) AF: 0.834 AC: 3962 AN: 4752

European-Finnish (FIN) AF: 0.786 AC: 8158 AN: 10384

Middle Eastern (MID) AF: 0.802 AC: 231 AN: 288

European-Non Finnish (NFE) AF: 0.835 AC: 56572 AN: 67782

Other (OTH) AF: 0.843 AC: 1769 AN: 2098

Alfa AF: 0.807 Hom.: 2730

Bravo AF: 0.858

Asia WGS AF: 0.852 AC: 2960 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.45
DANN	Benign	0.47
PhyloP100		-1.4
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: rs4940177; hg19: chr18-49868744;