18-52340854-T-C

Variant names:

• chr18-52340854-T-C
• rs9951523
• NM_005215.4:c.67T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005215.4(DCC):​c.67T>C​(p.Phe23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.986 in 1,613,996 control chromosomes in the GnomAD database, including 784,792 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74058 hom., cov: 31)
  • Exomes 𝑓: 0.99 (710734 hom.)
• Consequence: DCC NM_005215.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.22
• Publications: 34 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]

DCC Gene-Disease associations (from GenCC):

• mirror movements 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
• mirror movements 1 and/or agenesis of the corpus callosum

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• gaze palsy, familial horizontal, with progressive scoliosis, 2

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P
• connective tissue disorder

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• familial congenital mirror movements

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• colorectal cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)
• esophageal cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.8591564E-7).
• BP6: Variant 18-52340854-T-C is Benign according to our data. Variant chr18-52340854-T-C is described in ClinVar as Benign. ClinVar VariationId is 1255454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCC	NM_005215.4	MANE Select	c.67T>C	p.Phe23Leu	missense	Exon 1 of 29	NP_005206.2	P43146

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCC	ENST00000442544.7	TSL:1 MANE Select	c.67T>C	p.Phe23Leu	missense	Exon 1 of 29	ENSP00000389140.2	P43146

Frequencies

GnomAD3 genomes AF: 0.986 AC: 150040 AN: 152136 Hom.: 73999 Cov.: 31

Gnomad AFR AF: 0.997

Gnomad AMI AF: 0.979

Gnomad AMR AF: 0.990

Gnomad ASJ AF: 0.976

Gnomad EAS AF: 0.999

Gnomad SAS AF: 1.00

Gnomad FIN AF: 0.942

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.984

Gnomad OTH AF: 0.989

GnomAD2 exomes AF: 0.986 AC: 247863 AN: 251496 AF XY: 0.986

Gnomad AFR exome AF: 0.998

Gnomad AMR exome AF: 0.994

Gnomad ASJ exome AF: 0.974

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.948

Gnomad NFE exome AF: 0.983

Gnomad OTH exome AF: 0.988

GnomAD4 exome AF: 0.986 AC: 1441364 AN: 1461742 Hom.: 710734 Cov.: 47 AF XY: 0.986 AC XY: 717200 AN XY: 727186

African (AFR) AF: 0.998 AC: 33415 AN: 33478

American (AMR) AF: 0.994 AC: 44467 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.974 AC: 25459 AN: 26134

East Asian (EAS) AF: 1.00 AC: 39698 AN: 39700

South Asian (SAS) AF: 0.999 AC: 86152 AN: 86256

European-Finnish (FIN) AF: 0.953 AC: 50896 AN: 53420

Middle Eastern (MID) AF: 0.990 AC: 5708 AN: 5768

European-Non Finnish (NFE) AF: 0.986 AC: 1095994 AN: 1111870

Other (OTH) AF: 0.986 AC: 59575 AN: 60392

GnomAD4 genome AF: 0.986 AC: 150158 AN: 152254 Hom.: 74058 Cov.: 31 AF XY: 0.985 AC XY: 73308 AN XY: 74430

African (AFR) AF: 0.997 AC: 41454 AN: 41564

American (AMR) AF: 0.990 AC: 15139 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.976 AC: 3390 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5135 AN: 5138

South Asian (SAS) AF: 1.00 AC: 4822 AN: 4824

European-Finnish (FIN) AF: 0.942 AC: 9994 AN: 10604

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.984 AC: 66952 AN: 68038

Other (OTH) AF: 0.989 AC: 2091 AN: 2114

Alfa AF: 0.986 Hom.: 119986

Bravo AF: 0.989

ESP6500AA AF: 0.998 AC: 4397

ESP6500EA AF: 0.985 AC: 8468

ExAC AF: 0.986 AC: 119742

Asia WGS AF: 0.998 AC: 3472 AN: 3478

EpiCase AF: 0.985

EpiControl AF: 0.985

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Gaze palsy, familial horizontal, with progressive scoliosis, 2 (1)
-	-	1	Mirror movements 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	5.9e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.58	N
REVEL	Benign	0.099
Sift	Benign	1.0	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.011
MutPred		0.52		Loss of catalytic residue at F23 (P = 0.0085)
MPC		0.21
ClinPred		0.011	T
GERP RS		4.8
Varity_R		0.070
gMVP		0.32
Mutation Taster		=82/18	polymorphism (auto)

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: rs9951523; hg19: chr18-49867224; COSMIC: COSV107527802; COSMIC: COSV107527802;