rs141813053

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_005215.4(DCC):c.1409G>A(p.Gly470Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,614,060 control chromosomes in the GnomAD database, including 15 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 0.0029 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 12 hom. )

Consequence

DCC
NM_005215.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.29

Publications

10 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=0.009430081).

BP6

Variant 18-53157503-G-A is Benign according to our data. Variant chr18-53157503-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 187790.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00293 (447/152304) while in subpopulation NFE AF = 0.00517 (352/68032). AF 95% confidence interval is 0.00473. There are 3 homozygotes in GnomAd4. There are 198 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 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.1409G>A	p.Gly470Asp	missense	Exon 8 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.1409G>A	p.Gly470Asp	missense	Exon 8 of 29	ENSP00000389140.2	P43146
DCC	ENST00000581580.5	TSL:1	c.374G>A	p.Gly125Asp	missense	Exon 5 of 27	ENSP00000464582.1	J3QS93
DCC	ENST00000304775.12	TSL:1	n.1208G>A		non_coding_transcript_exon	Exon 7 of 19	ENSP00000304146.8	H0Y2Q5

Frequencies

GnomAD3 genomes

AF:

0.00294

AC:

447

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00517

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00287

AC:

720

AN:

251120

AF XY:

0.00281

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.00519

Gnomad OTH exome

AF:

0.00327

GnomAD4 exome

AF:

0.00434

AC:

6338

AN:

1461756

Hom.:

Cov.:

AF XY:

0.00419

AC XY:

3044

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.000717

AC:

AN:

33478

American (AMR)

AF:

0.00123

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.000765

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.000139

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00234

AC:

125

AN:

53378

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00525

AC:

5837

AN:

1111942

Other (OTH)

AF:

0.00407

AC:

246

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

343

686

1029

1372

1715

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

212

424

636

848

1060

<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:

0.00293

AC:

447

AN:

152304

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

198

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000962

AC:

AN:

41572

American (AMR)

AF:

0.00137

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00104

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00217

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00517

AC:

352

AN:

68032

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00451

Hom.:

Bravo

AF:

0.00275

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00640

AC:

ExAC

AF:

0.00317

AC:

385

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Amenorrhea (1)

Mirror movements 1 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.019

MetaRNN

Benign

0.0094

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.7

PhyloP100

7.3

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.34

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.72

Vest4

0.66

MVP

0.82

MPC

0.27

ClinPred

0.046

GERP RS

5.4

Varity_R

0.87

gMVP

0.49

Mutation Taster

=79/21

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