rs35691189

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

mirror movements 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina
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: Ambry Genetics, G2P
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)

DCC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

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

BP6

Variant 18-53322098-A-G is Benign according to our data. Variant chr18-53322098-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 187792.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 Unknown,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005215.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCC	NM_005215.4	MANE Select	c.2105A>G	p.Asn702Ser	missense	Exon 14 of 29	NP_005206.2	P43146

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DCC	ENST00000442544.7	TSL:1 MANE Select	c.2105A>G	p.Asn702Ser	missense	Exon 14 of 29	ENSP00000389140.2	P43146
DCC	ENST00000581580.5	TSL:1	c.1070A>G	p.Asn357Ser	missense	Exon 11 of 27	ENSP00000464582.1	J3QS93
DCC	ENST00000304775.12	TSL:1	n.1904A>G		non_coding_transcript_exon	Exon 13 of 19	ENSP00000304146.8	H0Y2Q5

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

GnomAD2 exomes

AF:

0.00279

AC:

702

AN:

251308

AF XY:

0.00283

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 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

African (AFR)

AF:

0.000599

AC:

AN:

33410

American (AMR)

AF:

0.000738

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26106

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39654

South Asian (SAS)

AF:

0.000511

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.00268

AC:

143

AN:

53418

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00507

AC:

5624

AN:

1108448

Other (OTH)

AF:

0.00297

AC:

179

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

276

551

827

1102

1378

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

216

432

648

864

1080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00272

AC:

414

AN:

152330

Hom.:

Cov.:

AF XY:

0.00248

AC XY:

185

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.000794

AC:

AN:

41586

American (AMR)

AF:

0.00209

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00226

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00466

AC:

317

AN:

68022

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00386

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

DCC-related disorder (1)

Mirror movements 1 (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

1.0

M_CAP

Benign

0.069

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.1

PhyloP100

8.5

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.72

MVP

0.82

MPC

0.65

ClinPred

0.066

GERP RS

4.5

Varity_R

0.76

gMVP

0.36

Mutation Taster

=62/38

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over