chr18-52752316-G-A

Position:

• chr18-52752316-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005215.4(DCC):​c.354G>A​(p.Glu118Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,613,824 control chromosomes in the GnomAD database, including 13,958 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (951 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13007 hom.)
• Consequence: DCC NM_005215.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.122

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 18-52752316-G-A is Benign according to our data. Variant chr18-52752316-G-A is described in ClinVar as [Benign]. Clinvar id is 1255455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.122 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCC	NM_005215.4	c.354G>A	p.Glu118Glu	synonymous_variant	2/29	ENST00000442544.7	NP_005206.2
DCC	XM_017025568.2	c.354G>A	p.Glu118Glu	synonymous_variant	2/29		XP_016881057.1
DCC	XM_017025569.2	c.354G>A	p.Glu118Glu	synonymous_variant	2/29		XP_016881058.1
DCC	XM_047437311.1	c.354G>A	p.Glu118Glu	synonymous_variant	2/29		XP_047293267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCC	ENST00000442544.7	c.354G>A	p.Glu118Glu	synonymous_variant	2/29	1	NM_005215.4	ENSP00000389140.2

Frequencies

GnomAD3 genomes AF: 0.0992 AC: 15084 AN: 152054 Hom.: 952 Cov.: 32

Gnomad AFR AF: 0.0411

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.0995

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.0720

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.139

GnomAD3 exomes AF: 0.107 AC: 26961 AN: 251114 Hom.: 1813 AF XY: 0.113 AC XY: 15342 AN XY: 135768

Gnomad AFR exome AF: 0.0367

Gnomad AMR exome AF: 0.0687

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.000815

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.0779

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.128 AC: 186592 AN: 1461652 Hom.: 13007 Cov.: 32 AF XY: 0.128 AC XY: 93281 AN XY: 727138

Gnomad4 AFR exome AF: 0.0379

Gnomad4 AMR exome AF: 0.0744

Gnomad4 ASJ exome AF: 0.216

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.0787

Gnomad4 NFE exome AF: 0.138

Gnomad4 OTH exome AF: 0.129

GnomAD4 genome AF: 0.0991 AC: 15077 AN: 152172 Hom.: 951 Cov.: 32 AF XY: 0.0951 AC XY: 7078 AN XY: 74390

Gnomad4 AFR AF: 0.0410

Gnomad4 AMR AF: 0.0993

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.0720

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.137

Alfa AF: 0.131 Hom.: 743

Bravo AF: 0.0979

Asia WGS AF: 0.0480 AC: 168 AN: 3478

EpiCase AF: 0.148

EpiControl AF: 0.157

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gaze palsy, familial horizontal, with progressive scoliosis, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Mirror movements 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

DCC-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.0
DANN	Benign	0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs13381333; hg19: chr18-50278686;