18-52340854-T-C

Position:

chr18-52340854-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.99 ( 74058 hom., cov: 31)

Exomes 𝑓: 0.99 ( 710734 hom. )

Consequence

DCC
NM_005215.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.22

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 1255454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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	Protein	UniProt
DCC	NM_005215.4 link	c.67T>C	p.Phe23Leu	missense_variant	1/29	ENST00000442544.7	NP_005206.2	P43146Q49AK4
DCC	XM_017025568.2 link	c.67T>C	p.Phe23Leu	missense_variant	1/29		XP_016881057.1
DCC	XM_017025569.2 link	c.67T>C	p.Phe23Leu	missense_variant	1/29		XP_016881058.1
DCC	XM_047437311.1 link	c.67T>C	p.Phe23Leu	missense_variant	1/29		XP_047293267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCC	ENST00000442544.7 link	c.67T>C	p.Phe23Leu	missense_variant	1/29	1	NM_005215.4	ENSP00000389140.2		P43146

Frequencies

GnomAD3 genomes

AF:

0.986

AC:

150040

AN:

152136

Hom.:

73999

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.986

AC XY:

717200

AN XY:

727186

show subpopulations

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.:

AF XY:

0.985

AC XY:

73308

AN XY:

74430

show subpopulations

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.046

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.17

MetaRNN

Benign

5.9e-7

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.48

PROVEAN

Benign

0.58

REVEL

Benign

0.099

Sift

Benign

1.0

Sift4G

Benign

0.66

Polyphen

0.0

Vest4

0.011

MutPred

0.52

Loss of catalytic residue at F23 (P = 0.0085);

MPC

0.21

ClinPred

0.011

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over