chr18-53526629-C-A

Variant names:

• chr18-53526629-C-A
• rs387906555
• NM_005215.4:c.4124C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_005215.4(DCC):​c.4124C>A​(p.Pro1375His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DCC NM_005215.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.70
• Publications: 5 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-53526629-C-A is Pathogenic according to our data. Variant chr18-53526629-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 17074.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3034373). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005215.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCC	NM_005215.4	MANE Select	c.4124C>A	p.Pro1375His	missense	Exon 28 of 29	NP_005206.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCC	ENST00000442544.7	TSL:1 MANE Select	c.4124C>A	p.Pro1375His	missense	Exon 28 of 29	ENSP00000389140.2
	DCC	ENST00000581580.5	TSL:1	c.3023C>A	p.Pro1008His	missense	Exon 25 of 27	ENSP00000464582.1
	DCC	ENST00000579702.1	TSL:3	n.209C>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Carcinoma of colon (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Benign	0.93
DEOGEN2	Benign	0.044	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.85	L
PhyloP100		6.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.093
Sift	Benign	0.58	T
Sift4G	Benign	0.67	T
Polyphen		0.60	P
Vest4		0.50
MutPred		0.48		Loss of glycosylation at P1375 (P = 0.0148)
MVP		0.42
MPC		0.63
ClinPred		0.77	D
GERP RS		5.5
Varity_R		0.17
gMVP		0.38
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906555; hg19: chr18-51052999; COSMIC: COSV101473444; COSMIC: COSV101473444;