dbSNP rs1555652216: DCC:p.Gln691Lys (chr18-53322064-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_005215.4(DCC):c.2071C>A(p.Gln691Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DCC
NM_005215.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 5.43

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 4 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

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCC	NM_005215.4 link	c.2071C>A	p.Gln691Lys	missense_variant	Exon 14 of 29	ENST00000442544.7	NP_005206.2	P43146Q49AK4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DCC	ENST00000442544.7 link	c.2071C>A	p.Gln691Lys	missense_variant	Exon 14 of 29	1	NM_005215.4	ENSP00000389140.2	P43146
DCC	ENST00000581580.5 link	c.1036C>A	p.Gln346Lys	missense_variant	Exon 11 of 27	1		ENSP00000464582.1	J3QS93
DCC	ENST00000304775.12 link	n.1870C>A		non_coding_transcript_exon_variant	Exon 13 of 19	1		ENSP00000304146.8	H0Y2Q5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1450830

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722550

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Gaze palsy, familial horizontal, with progressive scoliosis, 2

Uncertain:1

Jan 26, 2017

Tim Yu lab, Boston Children's Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

This variant is not found in public allele frequency databases, nor have any other variants affecting this amino acid position been reported. p.Gln691Lys alters a glutamine residue in the third fibronectin (FN) type III domain that is highly evolutionarily conserved, and this change was predicted to be deleterious by 5/7 algorithms applied -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.11

T;.;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.017

MetaRNN

Uncertain

0.55

D;D;D

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.96

L;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.8

N;.;.

REVEL

Uncertain

0.30

Sift

Uncertain

0.029

D;.;.

Sift4G

Uncertain

0.038

D;D;D

Polyphen

0.31

B;.;.

Vest4

0.59

MutPred

0.59

Gain of ubiquitination at Q691 (P = 0.0351);.;.;

MVP

0.94

MPC

0.34

ClinPred

0.88

GERP RS

5.6

Varity_R

0.58

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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