chr10-52316420-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012242.4(DKK1):ā€‹c.532A>Cā€‹(p.Met178Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

DKK1
NM_012242.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.286
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.047418475).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DKK1NM_012242.4 linkc.532A>C p.Met178Leu 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.532A>C p.Met178Leu missense_variant Exon 3 of 4 1 NM_012242.4 ENSP00000363081.3 O94907
DKK1ENST00000467359.5 linkn.532A>C non_coding_transcript_exon_variant Exon 2 of 2 2
DKK1ENST00000476752.1 linkn.181A>C non_coding_transcript_exon_variant Exon 2 of 3 2
DKK1ENST00000494277.5 linkn.155A>C non_coding_transcript_exon_variant Exon 2 of 4 5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461818
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727200
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 04, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.532A>C (p.M178L) alteration is located in exon 3 (coding exon 3) of the DKK1 gene. This alteration results from a A to C substitution at nucleotide position 532, causing the methionine (M) at amino acid position 178 to be replaced by a leucine (L). 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
0.074
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
12
DANN
Benign
0.82
DEOGEN2
Benign
0.41
T
Eigen
Benign
-0.69
Eigen_PC
Benign
-0.61
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.48
T
M_CAP
Benign
0.0051
T
MetaRNN
Benign
0.047
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.090
N
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.80
N
REVEL
Benign
0.018
Sift
Benign
1.0
T
Sift4G
Benign
0.46
T
Polyphen
0.0
B
Vest4
0.073
MutPred
0.21
Loss of MoRF binding (P = 0.1012);
MVP
0.42
MPC
0.41
ClinPred
0.035
T
GERP RS
2.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.044
gMVP
0.33

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: rs61757609; hg19: chr10-54076180; API