chr18-53157503-G-A

Position:

chr18-53157503-G-A

Variant summary

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

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

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=0.009430081).

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCC	NM_005215.4 linkuse as main transcript	c.1409G>A	p.Gly470Asp	missense_variant	8/29	ENST00000442544.7	NP_005206.2	P43146Q49AK4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DCC	ENST00000442544.7 linkuse as main transcript	c.1409G>A	p.Gly470Asp	missense_variant	8/29	1	NM_005215.4	ENSP00000389140.2	P43146
DCC	ENST00000581580.5 linkuse as main transcript	c.374G>A	p.Gly125Asp	missense_variant	5/27	1		ENSP00000464582.1	J3QS93
DCC	ENST00000304775.12 linkuse as main transcript	n.1208G>A		non_coding_transcript_exon_variant	7/19	1		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

GnomAD3 exomes

AF:

0.00287

AC:

720

AN:

251120

Hom.:

AF XY:

0.00281

AC XY:

382

AN XY:

135716

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 SAS exome

AF:

0.000163

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

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00234

Gnomad4 NFE exome

AF:

0.00525

Gnomad4 OTH exome

AF:

0.00407

GnomAD4 genome

AF:

0.00293

AC:

447

AN:

152304

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

198

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000962

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00217

Gnomad4 NFE

AF:

0.00517

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00479

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2Other: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	Jul 01, 2024	DCC: BS2 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Mirror movements 1

Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	European Non-Finnish population allele frequency is 0.4842% (rs141813053, 663/128942 alleles, 2 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.4.0, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -
not provided, no classification provided	literature only	GeneReviews	-	May be associated with a higher risk of CMM. -

Amenorrhea

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Mar 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.36

T;.;T

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.0094

T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.7

L;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-4.8

D;.;.

REVEL

Uncertain

0.34

Sift

Uncertain

0.0010

D;.;.

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

0.72

P;.;.

Vest4

0.66

MVP

0.82

MPC

0.27

ClinPred

0.046

GERP RS

5.4

Varity_R

0.87

gMVP

0.49

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