18-52906070-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4

The NM_005215.4(DCC):c.439G>A(p.Glu147Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,612,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

DCC
NM_005215.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.94

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 Uncertain_significance. Variant got 1 ACMG points.

PM1

In a domain Ig-like C2-type 2 (size 90) in uniprot entity DCC_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_005215.4

BP4

Computational evidence support a benign effect (MetaRNN=0.3176952).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DCC	NM_005215.4 linkuse as main transcript	c.439G>A	p.Glu147Lys	missense_variant	3/29	ENST00000442544.7
DCC	XM_017025568.2 linkuse as main transcript	c.439G>A	p.Glu147Lys	missense_variant	3/29
DCC	XM_017025569.2 linkuse as main transcript	c.439G>A	p.Glu147Lys	missense_variant	3/29
DCC	XM_047437311.1 linkuse as main transcript	c.439G>A	p.Glu147Lys	missense_variant	3/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCC	ENST00000442544.7 linkuse as main transcript	c.439G>A	p.Glu147Lys	missense_variant	3/29	1	NM_005215.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460396

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726666

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2023

The c.439G>A (p.E147K) alteration is located in exon 3 (coding exon 3) of the DCC gene. This alteration results from a G to A substitution at nucleotide position 439, causing the glutamic acid (E) at amino acid position 147 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.32

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

0.093

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.32

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.95

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.0

N;.

REVEL

Benign

0.12

Sift

Benign

0.069

T;.

Sift4G

Benign

0.22

T;T

Polyphen

0.017

B;.

Vest4

0.26

MutPred

0.62

Gain of ubiquitination at E147 (P = 0.0238);.;

MVP

0.62

MPC

0.21

ClinPred

0.64

GERP RS

5.7

Varity_R

0.35

gMVP

0.33

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