rs200099519

chr18-53305666-G-Achr18-53305666-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_005215.4(DCC):c.2000G>A(p.Arg667His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000796 in 1,613,934 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00052 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (11 hom.)
• Consequence: DCC NM_005215.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 9.42

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009708822).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000519 (79/152252) while in subpopulation SAS AF= 0.00768 (37/4818). AF 95% confidence interval is 0.00573. There are 1 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCC	NM_005215.4	c.2000G>A	p.Arg667His	missense_variant	13/29	ENST00000442544.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCC	ENST00000442544.7	c.2000G>A	p.Arg667His	missense_variant	13/29	1	NM_005215.4	P1
DCC	ENST00000581580.5	c.965G>A	p.Arg322His	missense_variant	10/27	1
DCC	ENST00000304775.12	c.1802G>A	p.Arg601His	missense_variant, NMD_transcript_variant	12/19	1

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152134 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00767

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00145 AC: 365 AN: 251178 Hom.: 3 AF XY: 0.00187 AC XY: 254 AN XY: 135722

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00964

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000405

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000824 AC: 1205 AN: 1461682 Hom.: 11 Cov.: 31 AF XY: 0.00108 AC XY: 788 AN XY: 727148

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00846

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000287

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152252 Hom.: 1 Cov.: 33 AF XY: 0.000564 AC XY: 42 AN XY: 74446

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00768

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000534 Hom.: 0

Bravo AF: 0.000291

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.00160 AC: 194

EpiCase AF: 0.000436

EpiControl AF: 0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	DCC: BS2 -

Mirror movements 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

May be associated with a higher risk of CMM. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.0097	T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.6	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.1	D;.;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.71
MutPred		0.47		Loss of MoRF binding (P = 0.0292);.;.;
MVP		0.80
MPC		0.79
ClinPred		0.10	T
GERP RS		5.6
Varity_R		0.85
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200099519; hg19: chr18-50832036; COSMIC: COSV59086117;