Genetic Variant DKK2:c.*954G>A (chr4-106923000-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_014421.3(DKK2):c.*954G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 152,012 control chromosomes in the GnomAD database, including 9,690 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 0.35 ( 9690 hom., cov: 33)

Exomes 𝑓: 0.50 ( 0 hom. )

Consequence

DKK2
NM_014421.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.835

Publications

12 publications found

Variant links:

Genes affected

DKK2 (HGNC:2892): (dickkopf WNT signaling pathway inhibitor 2) 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. It can act as either an agonist or antagonist of Wnt/beta-catenin signaling, depending on the cellular context and the presence of the co-factor kremen 2. Activity of this protein is also modulated by binding to the Wnt co-receptor LDL-receptor related protein 6 (LRP6). [provided by RefSeq, Jul 2008]

DKK2 links:

ENSG00000286147 (HGNC:):

ENSG00000286147 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKK2	NM_014421.3 link	c.*954G>A		3_prime_UTR_variant	Exon 4 of 4	ENST00000285311.8	NP_055236.1	Q9UBU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKK2	ENST00000285311.8 link	c.*954G>A		3_prime_UTR_variant	Exon 4 of 4	1	NM_014421.3	ENSP00000285311.3		Q9UBU2
ENSG00000286147	ENST00000650850.1 link	n.931+2812C>T		intron_variant	Intron 10 of 10

Frequencies

GnomAD3 genomes

AF:

0.351

AC:

53317

AN:

151892

Hom.:

9665

Cov.:

show subpopulations

Gnomad AFR

AF:

0.433

Gnomad AMI

AF:

0.266

Gnomad AMR

AF:

0.250

Gnomad ASJ

AF:

0.336

Gnomad EAS

AF:

0.273

Gnomad SAS

AF:

0.231

Gnomad FIN

AF:

0.380

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.337

Gnomad OTH

AF:

0.323

GnomAD4 exome

AF:

0.500

AC:

AN:

Hom.:

Cov.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.351

AC:

53391

AN:

152010

Hom.:

9690

Cov.:

AF XY:

0.348

AC XY:

25844

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.434

AC:

17977

AN:

41440

American (AMR)

AF:

0.250

AC:

3814

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.336

AC:

1164

AN:

3468

East Asian (EAS)

AF:

0.273

AC:

1407

AN:

5158

South Asian (SAS)

AF:

0.230

AC:

1110

AN:

4824

European-Finnish (FIN)

AF:

0.380

AC:

4018

AN:

10570

Middle Eastern (MID)

AF:

0.241

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.337

AC:

22894

AN:

67974

Other (OTH)

AF:

0.329

AC:

694

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1803

3606

5410

7213

9016

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

520

1040

1560

2080

2600

<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:

0.323

Hom.:

12972

Bravo

AF:

0.339

Asia WGS

AF:

0.252

AC:

875

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.31

(source)

DANN

Benign

0.43

PhyloP100

-0.83

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over