Variant 4-106925949-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_014421.3(DKK2):c.223G>A(p.Ala75Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000149 in 1,600,162 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

DKK2
NM_014421.3 missense, splice_region

Scores

Splicing: ADA: 0.3197

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.45

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:

DKK2 (HGNC:):

DKK2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1806151).

BS2

High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DKK2	NM_014421.3 linkuse as main transcript	c.223G>A	p.Ala75Thr	missense_variant, splice_region_variant	2/4	ENST00000285311.8	NP_055236.1	Q9UBU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DKK2	ENST00000285311.8 linkuse as main transcript	c.223G>A	p.Ala75Thr	missense_variant, splice_region_variant	2/4	1	NM_014421.3	ENSP00000285311.3		Q9UBU2

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

151860

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000177

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000143

AC:

AN:

237774

Hom.:

AF XY:

0.000171

AC XY:

AN XY:

128814

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000968

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000666

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000101

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.000153

AC:

222

AN:

1448302

Hom.:

Cov.:

AF XY:

0.000178

AC XY:

128

AN XY:

720730

show subpopulations

Gnomad4 AFR exome

AF:

0.0000308

Gnomad4 AMR exome

AF:

0.000123

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000747

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000128

Gnomad4 OTH exome

AF:

0.000184

GnomAD4 genome

AF:

0.000105

AC:

AN:

151860

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74164

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000177

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000158

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000124

AC:

EpiCase

AF:

0.0000549

EpiControl

AF:

0.000179

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2021

The c.223G>A (p.A75T) alteration is located in exon 2 (coding exon 2) of the DKK2 gene. This alteration results from a G to A substitution at nucleotide position 223, causing the alanine (A) at amino acid position 75 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.17

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.037

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.45

N;N

REVEL

Benign

0.092

Sift

Benign

0.15

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.42

B;.

Vest4

0.50

MVP

0.26

MPC

0.32

ClinPred

0.082

GERP RS

4.6

Varity_R

0.045

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.32

dbscSNV1_RF

Benign

0.42

SpliceAI score (max)

0.13

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over