rs2073664

Variant names:

• chr8-42374268-G-A
• rs2073664
• NM_014420.3:c.507C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_014420.3(DKK4):​c.507C>T​(p.Val169Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,613,456 control chromosomes in the GnomAD database, including 21,910 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 0.24 (8417 hom., cov: 32)
  • Exomes 𝑓: 0.098 (13493 hom.)
• Consequence: DKK4 NM_014420.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.316
• Publications: 28 publications found

Genes affected

DKK4 (HGNC:2894): (dickkopf WNT signaling pathway inhibitor 4) This gene encodes a protein that is a member of the dickkopf family. The secreted protein contains two cysteine rich regions and is involved in embryonic development through its interactions with the Wnt signaling pathway. Activity of this protein is modulated by binding to the Wnt co-receptor and the co-factor kremen 2. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP7: Synonymous conserved (PhyloP=0.316 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKK4	NM_014420.3	c.507C>T	p.Val169Val	synonymous_variant	Exon 4 of 4	ENST00000220812.3	NP_055235.1
DKK4	XM_011544488.3	c.507C>T	p.Val169Val	synonymous_variant	Exon 5 of 5		XP_011542790.1
DKK4	XM_017013316.2	c.507C>T	p.Val169Val	synonymous_variant	Exon 5 of 5		XP_016868805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKK4	ENST00000220812.3	c.507C>T	p.Val169Val	synonymous_variant	Exon 4 of 4	1	NM_014420.3	ENSP00000220812.2

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36098 AN: 151788 Hom.: 8383 Cov.: 32

Gnomad AFR AF: 0.608

Gnomad AMI AF: 0.0549

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.0642

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0714

Gnomad OTH AF: 0.194

GnomAD2 exomes AF: 0.137 AC: 34467 AN: 251080 AF XY: 0.132

Gnomad AFR exome AF: 0.617

Gnomad AMR exome AF: 0.0685

Gnomad ASJ exome AF: 0.0650

Gnomad EAS exome AF: 0.125

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.0718

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.0981 AC: 143410 AN: 1461550 Hom.: 13493 Cov.: 32 AF XY: 0.0997 AC XY: 72463 AN XY: 727082

African (AFR) AF: 0.627 AC: 20957 AN: 33432

American (AMR) AF: 0.0739 AC: 3299 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.0668 AC: 1746 AN: 26134

East Asian (EAS) AF: 0.149 AC: 5896 AN: 39694

South Asian (SAS) AF: 0.211 AC: 18173 AN: 86178

European-Finnish (FIN) AF: 0.159 AC: 8508 AN: 53420

Middle Eastern (MID) AF: 0.114 AC: 657 AN: 5756

European-Non Finnish (NFE) AF: 0.0689 AC: 76620 AN: 1111938

Other (OTH) AF: 0.125 AC: 7554 AN: 60372

GnomAD4 genome AF: 0.238 AC: 36175 AN: 151906 Hom.: 8417 Cov.: 32 AF XY: 0.240 AC XY: 17829 AN XY: 74252

African (AFR) AF: 0.608 AC: 25162 AN: 41386

American (AMR) AF: 0.111 AC: 1701 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0642 AC: 222 AN: 3460

East Asian (EAS) AF: 0.147 AC: 764 AN: 5184

South Asian (SAS) AF: 0.221 AC: 1064 AN: 4806

European-Finnish (FIN) AF: 0.181 AC: 1911 AN: 10538

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0714 AC: 4854 AN: 67958

Other (OTH) AF: 0.195 AC: 411 AN: 2108

Alfa AF: 0.137 Hom.: 2696

Bravo AF: 0.246

Asia WGS AF: 0.273 AC: 952 AN: 3478

EpiCase AF: 0.0650

EpiControl AF: 0.0679

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.6
DANN	Benign	0.78
PhyloP100		0.32
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2073664; hg19: chr8-42231786; COSMIC: COSV55184528; COSMIC: COSV55184528;