rs35691189

Positions:

chr18-53322098-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBS1BS2

The NM_005215.4(DCC):c.2105A>G(p.Asn702Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,610,312 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 19 hom. )

Consequence

DCC
NM_005215.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3O:1

Conservation

PhyloP100: 8.50

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 -10 ACMG points.

PM1

In a domain Fibronectin type-III 3 (size 93) in uniprot entity DCC_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_005215.4

BP4

Computational evidence support a benign effect (MetaRNN=0.017723113).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00272 (414/152330) while in subpopulation NFE AF= 0.00466 (317/68022). AF 95% confidence interval is 0.00424. There are 4 homozygotes in gnomad4. There are 185 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCC	NM_005215.4 linkuse as main transcript	c.2105A>G	p.Asn702Ser	missense_variant	14/29	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.2105A>G	p.Asn702Ser	missense_variant	14/29	1	NM_005215.4	ENSP00000389140	P1
DCC	ENST00000581580.5 linkuse as main transcript	c.1070A>G	p.Asn357Ser	missense_variant	11/27	1		ENSP00000464582
DCC	ENST00000304775.12 linkuse as main transcript	c.1907A>G	p.Asn636Ser	missense_variant, NMD_transcript_variant	13/19	1		ENSP00000304146

Frequencies

GnomAD3 genomes

AF:

0.00272

AC:

414

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00466

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00279

AC:

702

AN:

251308

Hom.:

AF XY:

0.00283

AC XY:

384

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00226

Gnomad NFE exome

AF:

0.00514

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00415

AC:

6055

AN:

1457982

Hom.:

Cov.:

AF XY:

0.00400

AC XY:

2905

AN XY:

725676

show subpopulations

Gnomad4 AFR exome

AF:

0.000599

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000511

Gnomad4 FIN exome

AF:

0.00268

Gnomad4 NFE exome

AF:

0.00507

Gnomad4 OTH exome

AF:

0.00297

GnomAD4 genome

AF:

0.00272

AC:

414

AN:

152330

Hom.:

Cov.:

AF XY:

0.00248

AC XY:

185

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.00466

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00370

Hom.:

Bravo

AF:

0.00261

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00453

AC:

ExAC

AF:

0.00306

AC:

372

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00414

EpiControl

AF:

0.00451

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	DCC: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in an individual with congenital mirror movements (Meneret et al., 2014); This variant is associated with the following publications: (PMID: 29366874, 24808016) -

Mirror movements 1

Uncertain:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	May be associated with a higher risk of CMM. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 14, 2023

- -

DCC-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 15, 2022

This variant is classified as likely 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

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Benign

0.79

DEOGEN2

Benign

0.38

T;.;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Benign

0.069

MetaRNN

Benign

0.018

T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.1

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.5

D;.;.

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0070

D;.;.

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.72

MVP

0.82

MPC

0.65

ClinPred

0.066

GERP RS

4.5

Varity_R

0.76

gMVP

0.36

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

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