10-52314997-A-G

Variant names:

• chr10-52314997-A-G
• rs2241529
• NM_012242.4:c.318A>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_012242.4(DKK1):​c.318A>G​(p.Ala106Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,601,528 control chromosomes in the GnomAD database, including 239,741 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.58 (25909 hom., cov: 30)
  • Exomes 𝑓: 0.54 (213832 hom.)
• Consequence: DKK1 NM_012242.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.42

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP7: Synonymous conserved (PhyloP=-3.42 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKK1	NM_012242.4	c.318A>G	p.Ala106Ala	synonymous_variant	Exon 2 of 4	ENST00000373970.4	NP_036374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKK1	ENST00000373970.4	c.318A>G	p.Ala106Ala	synonymous_variant	Exon 2 of 4	1	NM_012242.4	ENSP00000363081.3
DKK1	ENST00000467359.5	n.318A>G		non_coding_transcript_exon_variant	Exon 1 of 2	2
DKK1	ENST00000494277.5	n.-60A>G		upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.575 AC: 87200 AN: 151666 Hom.: 25862 Cov.: 30

Gnomad AFR AF: 0.697

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.726

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.585

GnomAD3 exomes AF: 0.514 AC: 126239 AN: 245404 Hom.: 33983 AF XY: 0.517 AC XY: 68764 AN XY: 132982

Gnomad AFR exome AF: 0.703

Gnomad AMR exome AF: 0.392

Gnomad ASJ exome AF: 0.646

Gnomad EAS exome AF: 0.275

Gnomad SAS exome AF: 0.517

Gnomad FIN exome AF: 0.484

Gnomad NFE exome AF: 0.556

Gnomad OTH exome AF: 0.545

GnomAD4 exome AF: 0.539 AC: 780710 AN: 1449744 Hom.: 213832 Cov.: 60 AF XY: 0.539 AC XY: 387333 AN XY: 719108

Gnomad4 AFR exome AF: 0.705

Gnomad4 AMR exome AF: 0.408

Gnomad4 ASJ exome AF: 0.653

Gnomad4 EAS exome AF: 0.311

Gnomad4 SAS exome AF: 0.514

Gnomad4 FIN exome AF: 0.484

Gnomad4 NFE exome AF: 0.547

Gnomad4 OTH exome AF: 0.551

GnomAD4 genome AF: 0.575 AC: 87301 AN: 151784 Hom.: 25909 Cov.: 30 AF XY: 0.569 AC XY: 42192 AN XY: 74184

Gnomad4 AFR AF: 0.698

Gnomad4 AMR AF: 0.500

Gnomad4 ASJ AF: 0.662

Gnomad4 EAS AF: 0.294

Gnomad4 SAS AF: 0.513

Gnomad4 FIN AF: 0.479

Gnomad4 NFE AF: 0.552

Gnomad4 OTH AF: 0.584

Alfa AF: 0.561 Hom.: 47083

Bravo AF: 0.582

Asia WGS AF: 0.449 AC: 1565 AN: 3478

EpiCase AF: 0.570

EpiControl AF: 0.573

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.5
DANN	Benign	0.73

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

Other links and lift over

dbSNP: rs2241529; hg19: chr10-54074757; COSMIC: COSV64760470; COSMIC: COSV64760470;