10-52315016-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_012242.4(DKK1):​c.337G>A​(p.Ala113Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000231 in 1,605,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 27)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

DKK1
NM_012242.4 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.0730
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.15030015).
BP6
Variant 10-52315016-G-A is Benign according to our data. Variant chr10-52315016-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2640478.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
BS2
High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DKK1NM_012242.4 linkc.337G>A p.Ala113Thr missense_variant Exon 2 of 4 ENST00000373970.4 NP_036374.1 O94907I1W660

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DKK1ENST00000373970.4 linkc.337G>A p.Ala113Thr missense_variant Exon 2 of 4 1 NM_012242.4 ENSP00000363081.3 O94907
DKK1ENST00000467359.5 linkn.337G>A non_coding_transcript_exon_variant Exon 1 of 2 2
DKK1ENST00000494277.5 linkn.-41G>A upstream_gene_variant 5

Frequencies

GnomAD3 genomes
AF:
0.0000855
AC:
13
AN:
152014
Hom.:
0
Cov.:
27
show subpopulations
Gnomad AFR
AF:
0.000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000202
AC:
5
AN:
247324
Hom.:
0
AF XY:
0.0000224
AC XY:
3
AN XY:
134000
show subpopulations
Gnomad AFR exome
AF:
0.000248
Gnomad AMR exome
AF:
0.0000292
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000165
AC:
24
AN:
1453042
Hom.:
0
Cov.:
35
AF XY:
0.0000153
AC XY:
11
AN XY:
721228
show subpopulations
Gnomad4 AFR exome
AF:
0.000541
Gnomad4 AMR exome
AF:
0.0000901
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.04e-7
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.0000855
AC:
13
AN:
152014
Hom.:
0
Cov.:
27
AF XY:
0.000121
AC XY:
9
AN XY:
74238
show subpopulations
Gnomad4 AFR
AF:
0.000242
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478
Bravo
AF:
0.000155
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 03, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.337G>A (p.A113T) alteration is located in exon 2 (coding exon 2) of the DKK1 gene. This alteration results from a G to A substitution at nucleotide position 337, causing the alanine (A) at amino acid position 113 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1
Nov 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

DKK1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.67
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
T
Eigen
Benign
-0.60
Eigen_PC
Benign
-0.49
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.70
T
M_CAP
Benign
0.0074
T
MetaRNN
Benign
0.15
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.79
N
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-0.26
N
REVEL
Benign
0.049
Sift
Benign
0.26
T
Sift4G
Benign
0.65
T
Polyphen
0.037
B
Vest4
0.086
MVP
0.46
MPC
0.47
ClinPred
0.065
T
GERP RS
2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.067
gMVP
0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs372651276; hg19: chr10-54074776; API