rs1569198

Variant names:

• chr10-52316511-A-G
• rs1569198
• NM_012242.4:c.548-43A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.485

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]

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKK1	NM_012242.4	c.548-43A>G		intron_variant	Intron 3 of 3	ENST00000373970.4	NP_036374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKK1	ENST00000373970.4	c.548-43A>G		intron_variant	Intron 3 of 3	1	NM_012242.4	ENSP00000363081.3
DKK1	ENST00000476752.1	n.197-43A>G		intron_variant	Intron 2 of 2	2
DKK1	ENST00000494277.5	n.171-43A>G		intron_variant	Intron 2 of 3	5
DKK1	ENST00000467359.5	n.*76A>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.415 AC: 62968 AN: 151910 Hom.: 13708 Cov.: 32

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

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.: 47 AF XY: 0.452 AC XY: 327607 AN XY: 725484

Gnomad4 AFR exome AF: 0.307 AC: 10223 AN: 33320

Gnomad4 AMR exome AF: 0.354 AC: 15769 AN: 44518

Gnomad4 ASJ exome AF: 0.609 AC: 15828 AN: 26000

Gnomad4 EAS exome AF: 0.205 AC: 8120 AN: 39658

Gnomad4 SAS exome AF: 0.321 AC: 27595 AN: 86022

Gnomad4 FIN exome AF: 0.452 AC: 24053 AN: 53204

Gnomad4 NFE exome AF: 0.477 AC: 529981 AN: 1110390

Gnomad4 Remaining exome AF: 0.451 AC: 27149 AN: 60248

GnomAD4 genome AF: 0.414 AC: 62985 AN: 152028 Hom.: 13712 Cov.: 32 AF XY: 0.411 AC XY: 30541 AN XY: 74308

Gnomad4 AFR AF: 0.312 AC: 0.312168 AN: 0.312168

Gnomad4 AMR AF: 0.410 AC: 0.410137 AN: 0.410137

Gnomad4 ASJ AF: 0.621 AC: 0.621326 AN: 0.621326

Gnomad4 EAS AF: 0.192 AC: 0.19189 AN: 0.19189

Gnomad4 SAS AF: 0.316 AC: 0.316445 AN: 0.316445

Gnomad4 FIN AF: 0.449 AC: 0.448837 AN: 0.448837

Gnomad4 NFE AF: 0.484 AC: 0.483651 AN: 0.483651

Gnomad4 OTH AF: 0.442 AC: 0.442289 AN: 0.442289

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.1
DANN	Benign	0.51
BranchPoint Hunter		3.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs1569198; hg19: chr10-54076271; COSMIC: COSV64759919; COSMIC: COSV64759919;