18-52906232-C-G

Position:

• chr18-52906232-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005215.4(DCC):​c.601C>G​(p.Arg201Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 1,613,528 control chromosomes in the GnomAD database, including 130,283 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12000 hom., cov: 32)
  • Exomes 𝑓: 0.39 (118283 hom.)
• Consequence: DCC NM_005215.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0770

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.275568E-5).
• BP6: Variant 18-52906232-C-G is Benign according to our data. Variant chr18-52906232-C-G is described in ClinVar as [Benign]. Clinvar id is 803493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-52906232-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCC	NM_005215.4	c.601C>G	p.Arg201Gly	missense_variant	3/29	ENST00000442544.7	NP_005206.2
DCC	XM_017025568.2	c.601C>G	p.Arg201Gly	missense_variant	3/29		XP_016881057.1
DCC	XM_017025569.2	c.601C>G	p.Arg201Gly	missense_variant	3/29		XP_016881058.1
DCC	XM_047437311.1	c.601C>G	p.Arg201Gly	missense_variant	3/29		XP_047293267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCC	ENST00000442544.7	c.601C>G	p.Arg201Gly	missense_variant	3/29	1	NM_005215.4	ENSP00000389140.2

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58743 AN: 151792 Hom.: 11990 Cov.: 32

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.546

Gnomad SAS AF: 0.635

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.393

GnomAD3 exomes AF: 0.452 AC: 113154 AN: 250512 Hom.: 27468 AF XY: 0.456 AC XY: 61759 AN XY: 135422

Gnomad AFR exome AF: 0.335

Gnomad AMR exome AF: 0.614

Gnomad ASJ exome AF: 0.502

Gnomad EAS exome AF: 0.554

Gnomad SAS exome AF: 0.626

Gnomad FIN exome AF: 0.387

Gnomad NFE exome AF: 0.363

Gnomad OTH exome AF: 0.449

GnomAD4 exome AF: 0.392 AC: 573444 AN: 1461616 Hom.: 118283 Cov.: 45 AF XY: 0.399 AC XY: 290411 AN XY: 727116

Gnomad4 AFR exome AF: 0.338

Gnomad4 AMR exome AF: 0.598

Gnomad4 ASJ exome AF: 0.493

Gnomad4 EAS exome AF: 0.608

Gnomad4 SAS exome AF: 0.623

Gnomad4 FIN exome AF: 0.395

Gnomad4 NFE exome AF: 0.356

Gnomad4 OTH exome AF: 0.414

GnomAD4 genome AF: 0.387 AC: 58788 AN: 151912 Hom.: 12000 Cov.: 32 AF XY: 0.396 AC XY: 29386 AN XY: 74236

Gnomad4 AFR AF: 0.336

Gnomad4 AMR AF: 0.492

Gnomad4 ASJ AF: 0.490

Gnomad4 EAS AF: 0.546

Gnomad4 SAS AF: 0.634

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.356

Gnomad4 OTH AF: 0.398

Alfa AF: 0.332 Hom.: 2751

Bravo AF: 0.392

TwinsUK AF: 0.358 AC: 1326

ALSPAC AF: 0.387 AC: 1490

ESP6500AA AF: 0.344 AC: 1517

ESP6500EA AF: 0.367 AC: 3157

ExAC AF: 0.444 AC: 53851

EpiCase AF: 0.383

EpiControl AF: 0.389

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2019	This variant is associated with the following publications: (PMID: 9440618) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Mirror movements 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.44	T;T
MetaRNN	Benign	0.000033	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.41	N;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.11
Sift	Benign	0.11	T;.
Sift4G	Benign	0.076	T;T
Polyphen		0.80	P;.
Vest4		0.67
MPC		0.26
ClinPred		0.035	T
GERP RS		-0.49
Varity_R		0.11
gMVP		0.67

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: rs2229080; hg19: chr18-50432602; COSMIC: COSV59089245;