10-52314615-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_012242.4(DKK1):ā€‹c.181A>Cā€‹(p.Ser61Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

DKK1
NM_012242.4 missense

Scores

1
8
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.54
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 Uncertain_significance. Variant got 3 ACMG points.

PM1
In a glycosylation_site O-linked (GalNAc...) serine (size 0) in uniprot entity DKK1_HUMAN
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3353808).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DKK1NM_012242.4 linkc.181A>C p.Ser61Arg missense_variant Exon 1 of 4 ENST00000373970.4 NP_036374.1 O94907I1W660

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DKK1ENST00000373970.4 linkc.181A>C p.Ser61Arg missense_variant Exon 1 of 4 1 NM_012242.4 ENSP00000363081.3 O94907

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152080
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000120
AC:
3
AN:
249268
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135428
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000267
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461108
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
726878
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:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152080
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74270
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
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
Alfa
AF:
0.0000312
Hom.:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1
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 01, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.181A>C (p.S61R) alteration is located in exon 1 (coding exon 1) of the DKK1 gene. This alteration results from a A to C substitution at nucleotide position 181, causing the serine (S) at amino acid position 61 to be replaced by an arginine (R). 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
Pathogenic
0.94
BayesDel_addAF
Benign
-0.061
T
BayesDel_noAF
Benign
-0.33
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
D
Eigen
Uncertain
0.22
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.73
T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.34
T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
1.0
L
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-0.72
N
REVEL
Benign
0.13
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.0050
D
Polyphen
0.97
D
Vest4
0.26
MutPred
0.37
Loss of glycosylation at S61 (P = 0.0095);
MVP
0.84
MPC
0.99
ClinPred
0.40
T
GERP RS
3.3
Varity_R
0.18
gMVP
0.86

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: rs372730677; hg19: chr10-54074375; API