Variant 10-52315038-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_012242.4(DKK1):c.359G>T(p.Arg120Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,603,066 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 26)

Exomes 𝑓: 0.0032 ( 9 hom. )

Consequence

DKK1
NM_012242.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 9.49

Variant links:

Genes affected

DKK1 (HGNC:2891): (dickkopf WNT signaling pathway inhibitor 1) This gene encodes a member of the dickkopf family of proteins. Members of this family are secreted proteins characterized by two cysteine-rich domains that mediate protein-protein interactions. The encoded protein binds to the LRP6 co-receptor and inhibits beta-catenin-dependent Wnt signaling. This gene plays a role in embryonic development and may be important in bone formation in adults. Elevated expression of this gene has been observed in numerous human cancers and this protein may promote proliferation, invasion and growth in cancer cell lines. [provided by RefSeq, Sep 2017]

DKK1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03161475).

BS2

High AC in GnomAd4 at 403 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKK1	NM_012242.4 link	c.359G>T	p.Arg120Leu	missense_variant	Exon 2 of 4	ENST00000373970.4	NP_036374.1	O94907I1W660

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DKK1	ENST00000373970.4 link	c.359G>T	p.Arg120Leu	missense_variant	Exon 2 of 4	1	NM_012242.4	ENSP00000363081.3	O94907
DKK1	ENST00000467359.5 link	n.359G>T		non_coding_transcript_exon_variant	Exon 1 of 2	2
DKK1	ENST00000494277.5 link	n.-19G>T		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00265

AC:

402

AN:

151932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000625

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00437

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.00286

AC:

701

AN:

244824

Hom.:

AF XY:

0.00302

AC XY:

400

AN XY:

132628

show subpopulations

Gnomad AFR exome

AF:

0.000622

Gnomad AMR exome

AF:

0.00192

Gnomad ASJ exome

AF:

0.00260

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.00228

Gnomad NFE exome

AF:

0.00458

Gnomad OTH exome

AF:

0.00303

GnomAD4 exome

AF:

0.00323

AC:

4681

AN:

1451016

Hom.:

Cov.:

AF XY:

0.00323

AC XY:

2328

AN XY:

720224

show subpopulations

Gnomad4 AFR exome

AF:

0.000663

Gnomad4 AMR exome

AF:

0.00202

Gnomad4 ASJ exome

AF:

0.00194

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000938

Gnomad4 FIN exome

AF:

0.00265

Gnomad4 NFE exome

AF:

0.00367

Gnomad4 OTH exome

AF:

0.00351

GnomAD4 genome

AF:

0.00265

AC:

403

AN:

152050

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

201

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.000723

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000625

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00438

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.00403

Hom.:

Bravo

AF:

0.00246

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00430

AC:

ExAC

AF:

0.00291

AC:

353

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

DKK1-related disorder

Benign:1

Dec 28, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.0028

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.032

MetaSVM

Benign

-0.28

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-6.2

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.87

MVP

0.85

MPC

1.5

ClinPred

0.038

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.87

gMVP

0.86

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