18-53499445-T-TGCTAC

Position:

• chr18-53499445-T-TGCTAC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000442544.7(DCC):​c.4047_4051dup​(p.Pro1351ArgfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DCC ENST00000442544.7 frameshift
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.55

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]

LINC01917 (HGNC:52736): (long intergenic non-protein coding RNA 1917)

LOC124904304 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCC	NM_005215.4	c.4047_4051dup	p.Pro1351ArgfsTer6	frameshift_variant	27/29	ENST00000442544.7	NP_005206.2
LOC124904304	XR_007066375.1	n.164+5777_164+5778insGTAGC		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCC	ENST00000442544.7	c.4047_4051dup	p.Pro1351ArgfsTer6	frameshift_variant	27/29	1	NM_005215.4	ENSP00000389140	P1
LINC01917	ENST00000650275.1	n.458+5777_458+5778insGTAGC		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

DCC-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2024

The DCC c.4047_4051dup5 variant is predicted to result in a frameshift and premature protein termination (p.Pro1351Argfs*6). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Only one frameshift variant has been reported downstream of p.Pro1351 (p.Ser1406Lysfs*22) in five members of a family; four members were reported as having congenital mirror movements and one member was reported as not affected (Family 4 in Bierhals et al. 2018. PubMed ID: 29366874). Although we suspect that the p.Pro1351Argfs*6 variant may be pathogenic, at this time, its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-51025815;