dbSNP rs2291598: DKK3:p.Val236Met (chr11-11965933-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001018057.2(DKK3):c.706G>A(p.Val236Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,613,592 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V236G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000048 ( 1 hom. )

Consequence

DKK3
NM_001018057.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.196

Publications

3 publications found

Variant links:

Genes affected

DKK3 (HGNC:2893): (dickkopf WNT signaling pathway inhibitor 3) This gene encodes a protein that is a member of the dickkopf family. The secreted protein contains two cysteine rich regions and is involved in embryonic development through its interactions with the Wnt signaling pathway. The expression of this gene is decreased in a variety of cancer cell lines and it may function as a tumor suppressor gene. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

DKK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.024234384).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018057.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DKK3	NM_001018057.2	MANE Select	c.706G>A	p.Val236Met	missense	Exon 6 of 7	NP_001018067.1	Q9UBP4
DKK3	NM_001330220.3		c.706G>A	p.Val236Met	missense	Exon 7 of 8	NP_001317149.1	F6SYF8
DKK3	NM_013253.5		c.706G>A	p.Val236Met	missense	Exon 7 of 8	NP_037385.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DKK3	ENST00000683431.1	MANE Select	c.706G>A	p.Val236Met	missense	Exon 6 of 7	ENSP00000506835.1	Q9UBP4
DKK3	ENST00000326932.8	TSL:1	c.706G>A	p.Val236Met	missense	Exon 7 of 8	ENSP00000314910.4	Q9UBP4
DKK3	ENST00000396505.7	TSL:1	c.706G>A	p.Val236Met	missense	Exon 7 of 8	ENSP00000379762.2	Q9UBP4

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000120

AC:

AN:

249132

AF XY:

0.000156

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0000477

Gnomad NFE exome

AF:

0.0000622

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1461262

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

726932

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000918

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52974

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1111918

Other (OTH)

AF:

0.0000994

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000118

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41576

American (AMR)

AF:

0.00

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5156

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000222

Hom.:

Bravo

AF:

0.000117

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000989

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.65

M_CAP

Benign

0.0043

MetaRNN

Benign

0.024

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

PhyloP100

0.20

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.34

REVEL

Benign

0.033

Sift

Benign

0.10

Sift4G

Benign

0.17

Polyphen

0.29

Vest4

0.30

MVP

0.32

MPC

0.37

ClinPred

0.019

GERP RS

2.9

Varity_R

0.030

gMVP

0.45

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over