Genetic Variant DKK1:c.548-4G>T (chr10-52316550-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The NM_012242.4(DKK1):c.548-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000238 in 1,613,576 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 2 hom. )

Consequence

DKK1
NM_012242.4 splice_region, intron

Scores

Splicing: ADA: 0.00001793

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.16

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 (BayesDel_noAF=-0.91).

BS2

High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKK1	NM_012242.4 link	c.548-4G>T		splice_region_variant, intron_variant	Intron 3 of 3	ENST00000373970.4	NP_036374.1	O94907I1W660

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
DKK1	ENST00000373970.4 link	c.548-4G>T	splice_region_variant, intron_variant	Intron 3 of 3	1	NM_012242.4	ENSP00000363081.3	O94907
DKK1	ENST00000476752.1 link	n.197-4G>T	splice_region_variant, intron_variant	Intron 2 of 2	2
DKK1	ENST00000494277.5 link	n.171-4G>T	splice_region_variant, intron_variant	Intron 2 of 3	5
DKK1	ENST00000467359.5 link	n.*115G>T	downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00619

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000594

AC:

149

AN:

250922

Hom.:

AF XY:

0.000583

AC XY:

AN XY:

135590

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00631

Gnomad SAS exome

AF:

0.000753

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000235

AC:

344

AN:

1461380

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

189

AN XY:

726946

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00526

Gnomad4 SAS exome

AF:

0.000824

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.0000387

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000263

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00620

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000410

Hom.:

Bravo

AF:

0.000317

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.41

DANN

Benign

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000018

dbscSNV1_RF

Benign

0.010

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

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