Genetic Variant DKK2:n.65T>C (chr4-107035748-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 ENST00000510534.1(DKK2):n.65T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0985 in 687,612 control chromosomes in the GnomAD database, including 4,114 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 0.093 ( 866 hom., cov: 32)

Exomes 𝑓: 0.10 ( 3248 hom. )

Consequence

DKK2
ENST00000510534.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.84

Publications

6 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:

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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=-0.75).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKK2	NM_014421.3 link	c.-157T>C		5_prime_UTR_variant	Exon 1 of 4	ENST00000285311.8	NP_055236.1	Q9UBU2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
DKK2	ENST00000510534.1 link	n.65T>C	non_coding_transcript_exon_variant	Exon 1 of 3	1
DKK2	ENST00000285311.8 link	c.-157T>C	5_prime_UTR_variant	Exon 1 of 4	1	NM_014421.3	ENSP00000285311.3	Q9UBU2
DKK2	ENST00000513208.5 link	c.-78-109799T>C	intron_variant	Intron 2 of 4	1		ENSP00000421255.1	D6RGF1
DKK2	ENST00000510463.1 link	c.84+92194T>C	intron_variant	Intron 3 of 5	3		ENSP00000423797.1	D6RCC2

Frequencies

GnomAD3 genomes

AF:

0.0925

AC:

14070

AN:

152066

Hom.:

864

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0451

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.126

Gnomad ASJ

AF:

0.0689

Gnomad EAS

AF:

0.231

Gnomad SAS

AF:

0.137

Gnomad FIN

AF:

0.192

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0869

Gnomad OTH

AF:

0.0951

GnomAD4 exome

AF:

0.100

AC:

53674

AN:

535426

Hom.:

3248

Cov.:

AF XY:

0.101

AC XY:

28103

AN XY:

279268

show subpopulations

African (AFR)

AF:

0.0405

AC:

579

AN:

14282

American (AMR)

AF:

0.141

AC:

2974

AN:

21166

Ashkenazi Jewish (ASJ)

AF:

0.0670

AC:

970

AN:

14480

East Asian (EAS)

AF:

0.175

AC:

5537

AN:

31628

South Asian (SAS)

AF:

0.121

AC:

5906

AN:

48734

European-Finnish (FIN)

AF:

0.190

AC:

5665

AN:

29818

Middle Eastern (MID)

AF:

0.0902

AC:

195

AN:

2162

European-Non Finnish (NFE)

AF:

0.0837

AC:

28794

AN:

344220

Other (OTH)

AF:

0.106

AC:

3054

AN:

28936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

2585

5170

7754

10339

12924

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

430

860

1290

1720

2150

<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:

0.0925

AC:

14078

AN:

152186

Hom.:

866

Cov.:

AF XY:

0.0988

AC XY:

7351

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0451

AC:

1873

AN:

41544

American (AMR)

AF:

0.126

AC:

1934

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0689

AC:

239

AN:

3470

East Asian (EAS)

AF:

0.231

AC:

1184

AN:

5132

South Asian (SAS)

AF:

0.137

AC:

662

AN:

4826

European-Finnish (FIN)

AF:

0.192

AC:

2039

AN:

10608

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0869

AC:

5908

AN:

67982

Other (OTH)

AF:

0.0959

AC:

203

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

653

1306

1958

2611

3264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

158

316

474

632

790

<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:

0.0833

Hom.:

656

Bravo

AF:

0.0839

Asia WGS

AF:

0.217

AC:

756

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.63

PhyloP100

1.8

Mutation Taster

=99/1

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over