Genetic Variant DKK1:p.Ala106Ala (chr10-52314997-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_012242.4(DKK1):c.318A>G(p.Ala106Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,601,528 control chromosomes in the GnomAD database, including 239,741 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.58 ( 25909 hom., cov: 30)

Exomes 𝑓: 0.54 ( 213832 hom. )

Consequence

DKK1
NM_012242.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.42

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 was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP7

Synonymous conserved (PhyloP=-3.42 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKK1	NM_012242.4 link	c.318A>G	p.Ala106Ala	synonymous_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.318A>G	p.Ala106Ala	synonymous_variant	Exon 2 of 4	1	NM_012242.4	ENSP00000363081.3	O94907
DKK1	ENST00000467359.5 link	n.318A>G		non_coding_transcript_exon_variant	Exon 1 of 2	2
DKK1	ENST00000494277.5 link	n.-60A>G		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.575

AC:

87200

AN:

151666

Hom.:

25862

Cov.:

show subpopulations

Gnomad AFR

AF:

0.697

Gnomad AMI

AF:

0.595

Gnomad AMR

AF:

0.501

Gnomad ASJ

AF:

0.662

Gnomad EAS

AF:

0.294

Gnomad SAS

AF:

0.512

Gnomad FIN

AF:

0.479

Gnomad MID

AF:

0.726

Gnomad NFE

AF:

0.552

Gnomad OTH

AF:

0.585

GnomAD2 exomes

AF:

0.514

AC:

126239

AN:

245404

AF XY:

0.517

show subpopulations

Gnomad AFR exome

AF:

0.703

Gnomad AMR exome

AF:

0.392

Gnomad ASJ exome

AF:

0.646

Gnomad EAS exome

AF:

0.275

Gnomad FIN exome

AF:

0.484

Gnomad NFE exome

AF:

0.556

Gnomad OTH exome

AF:

0.545

GnomAD4 exome

AF:

0.539

AC:

780710

AN:

1449744

Hom.:

213832

Cov.:

AF XY:

0.539

AC XY:

387333

AN XY:

719108

show subpopulations

Gnomad4 AFR exome

AF:

0.705

AC:

23421

AN:

33242

Gnomad4 AMR exome

AF:

0.408

AC:

18041

AN:

44164

Gnomad4 ASJ exome

AF:

0.653

AC:

16928

AN:

25908

Gnomad4 EAS exome

AF:

0.311

AC:

12215

AN:

39298

Gnomad4 SAS exome

AF:

0.514

AC:

43905

AN:

85356

Gnomad4 FIN exome

AF:

0.484

AC:

25507

AN:

52730

Gnomad4 NFE exome

AF:

0.547

AC:

603662

AN:

1103558

Gnomad4 Remaining exome

AF:

0.551

AC:

32957

AN:

59780

Heterozygous variant carriers

19981

39961

59942

79922

99903

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

17046

34092

51138

68184

85230

<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:

0.575

AC:

87301

AN:

151784

Hom.:

25909

Cov.:

AF XY:

0.569

AC XY:

42192

AN XY:

74184

show subpopulations

Gnomad4 AFR

AF:

0.698

AC:

0.69756

AN:

0.69756

Gnomad4 AMR

AF:

0.500

AC:

0.500262

AN:

0.500262

Gnomad4 ASJ

AF:

0.662

AC:

0.662341

AN:

0.662341

Gnomad4 EAS

AF:

0.294

AC:

0.294244

AN:

0.294244

Gnomad4 SAS

AF:

0.513

AC:

0.512901

AN:

0.512901

Gnomad4 FIN

AF:

0.479

AC:

0.479305

AN:

0.479305

Gnomad4 NFE

AF:

0.552

AC:

0.552208

AN:

0.552208

Gnomad4 OTH

AF:

0.584

AC:

0.58436

AN:

0.58436

Heterozygous variant carriers

1776

3553

5329

7106

8882

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

722

1444

2166

2888

3610

<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:

0.561

Hom.:

67641

Bravo

AF:

0.582

Asia WGS

AF:

0.449

AC:

1565

AN:

3478

EpiCase

AF:

0.570

EpiControl

AF:

0.573

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

6.5

DANN

Benign

0.73

Mutation Taster

=100/0

polymorphism (auto)

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over