rs1555682265

Positions:

• chr18-52923795-TGTTTCTG-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_005215.4(DCC):​c.788_794del​(p.Val263AlafsTer36) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DCC NM_005215.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.44

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-52923795-TGTTTCTG-T is Pathogenic according to our data. Variant chr18-52923795-TGTTTCTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 446724.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-52923795-TGTTTCTG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCC	NM_005215.4	c.788_794del	p.Val263AlafsTer36	frameshift_variant	4/29	ENST00000442544.7	NP_005206.2
DCC	XM_017025568.2	c.788_794del	p.Val263AlafsTer36	frameshift_variant	4/29		XP_016881057.1
DCC	XM_017025569.2	c.788_794del	p.Val263AlafsTer36	frameshift_variant	4/29		XP_016881058.1
DCC	XM_047437311.1	c.788_794del	p.Val263AlafsTer36	frameshift_variant	4/29		XP_047293267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCC	ENST00000442544.7	c.788_794del	p.Val263AlafsTer36	frameshift_variant	4/29	1	NM_005215.4	ENSP00000389140	P1
DCC	ENST00000304775.12	c.589_595del	p.Val197AlafsTer36	frameshift_variant, NMD_transcript_variant	3/19	1		ENSP00000304146
DCC	ENST00000579883.1			non_coding_transcript_exon_variant	1/3	4
DCC	ENST00000584710.5	n.14_20del		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Gaze palsy, familial horizontal, with progressive scoliosis, 2 Pathogenic:2

Pathogenic, no assertion criteria provided	research	Tim Yu lab, Boston Children's Hospital	Jan 26, 2017	Homozygous deletion identified in affected individual. Both parents were carriers. This variant is absent from public databases (Exome Aggregation Consortium, Exome Variant Server, dbSNP146, 1000 Genomes Project) as well as an internal exome database of >1000 Middle Eastern samples. It is at amino acid position 263 (of 1447) in the third immunoglobulin repeat, resulting in frameshift and premature termination 36 amino acids downstream (p.Val263Alafs*36). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 02, 2019	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555682265; hg19: chr18-50450165;