rs3733635

Positions:

• chr4-107035748-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014421.3(DKK2):​c.-157T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0985 in 687,612 control chromosomes in the GnomAD database, including 4,114 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 0.093 (866 hom., cov: 32)
  • Exomes 𝑓: 0.10 (3248 hom.)
• Consequence: DKK2 NM_014421.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.84

Genes affected

DKK2 (HGNC:2892): (dickkopf WNT signaling pathway inhibitor 2) 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. It can act as either an agonist or antagonist of Wnt/beta-catenin signaling, depending on the cellular context and the presence of the co-factor kremen 2. Activity of this protein is also modulated by binding to the Wnt co-receptor LDL-receptor related protein 6 (LRP6). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DKK2	NM_014421.3	c.-157T>C		5_prime_UTR_variant	1/4	ENST00000285311.8	NP_055236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DKK2	ENST00000285311.8	c.-157T>C		5_prime_UTR_variant	1/4	1	NM_014421.3	ENSP00000285311	P1
DKK2	ENST00000513208.5	c.-78-109799T>C		intron_variant		1		ENSP00000421255
DKK2	ENST00000510534.1	n.65T>C		non_coding_transcript_exon_variant	1/3	1
DKK2	ENST00000510463.1	c.84+92194T>C		intron_variant		3		ENSP00000423797

Frequencies

GnomAD3 genomes AF: 0.0925 AC: 14070 AN: 152066 Hom.: 864 Cov.: 32

Gnomad AFR AF: 0.0451

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.0689

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0869

Gnomad OTH AF: 0.0951

GnomAD4 exome AF: 0.100 AC: 53674 AN: 535426 Hom.: 3248 Cov.: 6 AF XY: 0.101 AC XY: 28103 AN XY: 279268

Gnomad4 AFR exome AF: 0.0405

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.0670

Gnomad4 EAS exome AF: 0.175

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.190

Gnomad4 NFE exome AF: 0.0837

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.0925 AC: 14078 AN: 152186 Hom.: 866 Cov.: 32 AF XY: 0.0988 AC XY: 7351 AN XY: 74402

Gnomad4 AFR AF: 0.0451

Gnomad4 AMR AF: 0.126

Gnomad4 ASJ AF: 0.0689

Gnomad4 EAS AF: 0.231

Gnomad4 SAS AF: 0.137

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.0869

Gnomad4 OTH AF: 0.0959

Alfa AF: 0.0840 Hom.: 545

Bravo AF: 0.0839

Asia WGS AF: 0.217 AC: 756 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	12
DANN	Benign	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

LitVar

Other links and lift over

dbSNP: rs3733635; hg19: chr4-107956905;