10-52316312-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012242.4(DKK1):​c.424G>A​(p.Asp142Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

DKK1
NM_012242.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.68
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.22647694).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DKK1NM_012242.4 linkc.424G>A p.Asp142Asn missense_variant Exon 3 of 4 ENST00000373970.4 NP_036374.1 O94907I1W660

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DKK1ENST00000373970.4 linkc.424G>A p.Asp142Asn missense_variant Exon 3 of 4 1 NM_012242.4 ENSP00000363081.3 O94907
DKK1ENST00000467359.5 linkn.424G>A non_coding_transcript_exon_variant Exon 2 of 2 2
DKK1ENST00000476752.1 linkn.73G>A non_coding_transcript_exon_variant Exon 2 of 3 2
DKK1ENST00000494277.5 linkn.47G>A non_coding_transcript_exon_variant Exon 2 of 4 5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 01, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.424G>A (p.D142N) alteration is located in exon 3 (coding exon 3) of the DKK1 gene. This alteration results from a G to A substitution at nucleotide position 424, causing the aspartic acid (D) at amino acid position 142 to be replaced by an asparagine (N). 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
0.13
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.62
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.65
D
Eigen
Benign
0.056
Eigen_PC
Uncertain
0.22
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.79
T
M_CAP
Benign
0.0096
T
MetaRNN
Benign
0.23
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.5
L
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-2.2
N
REVEL
Benign
0.088
Sift
Benign
0.038
D
Sift4G
Uncertain
0.059
T
Polyphen
0.12
B
Vest4
0.30
MutPred
0.22
Loss of catalytic residue at D142 (P = 0.105);
MVP
0.71
MPC
1.0
ClinPred
0.89
D
GERP RS
5.7
Varity_R
0.16
gMVP
0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-54076072; API