rs200099519

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The ENST00000442544.7(DCC):c.2000G>A(p.Arg667His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000796 in 1,613,934 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00052 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00082 ( 11 hom. )

Consequence

DCC
ENST00000442544.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 9.42

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009708822).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000519 (79/152252) while in subpopulation SAS AF= 0.00768 (37/4818). AF 95% confidence interval is 0.00573. There are 1 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCC	NM_005215.4 linkuse as main transcript	c.2000G>A	p.Arg667His	missense_variant	13/29	ENST00000442544.7	NP_005206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DCC	ENST00000442544.7 linkuse as main transcript	c.2000G>A	p.Arg667His	missense_variant	13/29	1	NM_005215.4	ENSP00000389140	P1
DCC	ENST00000581580.5 linkuse as main transcript	c.965G>A	p.Arg322His	missense_variant	10/27	1		ENSP00000464582
DCC	ENST00000304775.12 linkuse as main transcript	c.1802G>A	p.Arg601His	missense_variant, NMD_transcript_variant	12/19	1		ENSP00000304146

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00767

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00145

AC:

365

AN:

251178

Hom.:

AF XY:

0.00187

AC XY:

254

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00964

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000405

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000824

AC:

1205

AN:

1461682

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

788

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00846

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000287

Gnomad4 OTH exome

AF:

0.00121

GnomAD4 genome

AF:

0.000519

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00768

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000534

Hom.:

Bravo

AF:

0.000291

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.00160

AC:

194

EpiCase

AF:

0.000436

EpiControl

AF:

0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	DCC: BS2 -

Mirror movements 1

Other:1

not provided, no classification provided

literature only

GeneReviews

May be associated with a higher risk of CMM. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

T;.;T

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.0097

T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.6

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-4.1

D;.;.

REVEL

Uncertain

0.42

Sift

Uncertain

0.0010

D;.;.

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.71

MutPred

0.47

Loss of MoRF binding (P = 0.0292);.;.;

MVP

0.80

MPC

0.79

ClinPred

0.10

GERP RS

5.6

Varity_R

0.85

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over