chr18-53322064-C-A

Variant names:

• chr18-53322064-C-A
• rs1555652216
• NM_005215.4:c.2071C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q691E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DCC NM_005215.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.43

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• 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	c.2071C>A	p.Gln691Lys	missense_variant	Exon 14 of 29	ENST00000442544.7	NP_005206.2

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450830 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

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	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T;.;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.96	L;.;.
PrimateAI	Uncertain	0.67	T
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	D
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

Other links and lift over

dbSNP: rs1555652216; hg19: chr18-50848434;