18-52340854-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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, single submitter B:2
• Conservation: PhyloP100: 1.22

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 Benign. Variant got -14 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 id is 1255454.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-52340854-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCC	NM_005215.4	c.67T>C	p.Phe23Leu	missense_variant	1/29	ENST00000442544.7
DCC	XM_017025568.2	c.67T>C	p.Phe23Leu	missense_variant	1/29
DCC	XM_017025569.2	c.67T>C	p.Phe23Leu	missense_variant	1/29
DCC	XM_047437311.1	c.67T>C	p.Phe23Leu	missense_variant	1/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCC	ENST00000442544.7	c.67T>C	p.Phe23Leu	missense_variant	1/29	1	NM_005215.4	P1

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

GnomAD3 exomes AF: 0.986 AC: 247863 AN: 251496 Hom.: 122177 AF XY: 0.986 AC XY: 133985 AN XY: 135922

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 SAS exome AF: 0.999

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

Gnomad4 AFR exome AF: 0.998

Gnomad4 AMR exome AF: 0.994

Gnomad4 ASJ exome AF: 0.974

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 0.953

Gnomad4 NFE exome AF: 0.986

Gnomad4 OTH exome AF: 0.986

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

Gnomad4 AFR AF: 0.997

Gnomad4 AMR AF: 0.990

Gnomad4 ASJ AF: 0.976

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 0.942

Gnomad4 NFE AF: 0.984

Gnomad4 OTH AF: 0.989

Alfa AF: 0.985 Hom.: 78264

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Gaze palsy, familial horizontal, with progressive scoliosis, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Mirror movements 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs9951523; hg19: chr18-49867224;