dbSNP rs1569198: DKK1:c.548-43A>G (chr10-52316511-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_012242.4(DKK1):c.548-43A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 1,611,148 control chromosomes in the GnomAD database, including 168,418 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. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.41 ( 13712 hom., cov: 32)

Exomes 𝑓: 0.45 ( 154706 hom. )

Consequence

DKK1
NM_012242.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.485

Publications

31 publications found

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 -12 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.479 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012242.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKK1	NM_012242.4	MANE Select	c.548-43A>G		intron	N/A	NP_036374.1	I1W660

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DKK1	ENST00000373970.4	TSL:1 MANE Select	c.548-43A>G	intron	N/A	ENSP00000363081.3	O94907
DKK1	ENST00000476752.1	TSL:2	n.197-43A>G	intron	N/A
DKK1	ENST00000494277.5	TSL:5	n.171-43A>G	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.415

AC:

62968

AN:

151910

Hom.:

13708

Cov.:

show subpopulations

Gnomad AFR

AF:

0.312

Gnomad AMI

AF:

0.425

Gnomad AMR

AF:

0.410

Gnomad ASJ

AF:

0.621

Gnomad EAS

AF:

0.192

Gnomad SAS

AF:

0.315

Gnomad FIN

AF:

0.449

Gnomad MID

AF:

0.599

Gnomad NFE

AF:

0.484

Gnomad OTH

AF:

0.446

GnomAD2 exomes

AF:

0.414

AC:

103440

AN:

250088

AF XY:

0.416

show subpopulations

Gnomad AFR exome

AF:

0.310

Gnomad AMR exome

AF:

0.342

Gnomad ASJ exome

AF:

0.608

Gnomad EAS exome

AF:

0.181

Gnomad FIN exome

AF:

0.452

Gnomad NFE exome

AF:

0.487

Gnomad OTH exome

AF:

0.460

GnomAD4 exome

AF:

0.454

AC:

662238

AN:

1459120

Hom.:

154706

Cov.:

AF XY:

0.452

AC XY:

327607

AN XY:

725484

show subpopulations

African (AFR)

AF:

0.307

AC:

10223

AN:

33320

American (AMR)

AF:

0.354

AC:

15769

AN:

44518

Ashkenazi Jewish (ASJ)

AF:

0.609

AC:

15828

AN:

26000

East Asian (EAS)

AF:

0.205

AC:

8120

AN:

39658

South Asian (SAS)

AF:

0.321

AC:

27595

AN:

86022

European-Finnish (FIN)

AF:

0.452

AC:

24053

AN:

53204

Middle Eastern (MID)

AF:

0.611

AC:

3520

AN:

5760

European-Non Finnish (NFE)

AF:

0.477

AC:

529981

AN:

1110390

Other (OTH)

AF:

0.451

AC:

27149

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

20191

40383

60574

80766

100957

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15380

30760

46140

61520

76900

<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:

0.414

AC:

62985

AN:

152028

Hom.:

13712

Cov.:

AF XY:

0.411

AC XY:

30541

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.312

AC:

12940

AN:

41452

American (AMR)

AF:

0.410

AC:

6271

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.621

AC:

2156

AN:

3470

East Asian (EAS)

AF:

0.192

AC:

989

AN:

5154

South Asian (SAS)

AF:

0.316

AC:

1524

AN:

4816

European-Finnish (FIN)

AF:

0.449

AC:

4746

AN:

10574

Middle Eastern (MID)

AF:

0.582

AC:

170

AN:

292

European-Non Finnish (NFE)

AF:

0.484

AC:

32866

AN:

67954

Other (OTH)

AF:

0.442

AC:

935

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1849

3698

5546

7395

9244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

586

1172

1758

2344

2930

<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:

0.459

Hom.:

6087

Bravo

AF:

0.409

Asia WGS

AF:

0.227

AC:

793

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

2.1

(source)

DANN

Benign

0.51

PhyloP100

0.48

BranchPoint Hunter

3.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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