4-106924637-C-T

Variant names:

• chr4-106924637-C-T
• rs17037102
• NM_014421.3:c.437G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014421.3(DKK2):​c.437G>A​(p.Arg146Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,613,500 control chromosomes in the GnomAD database, including 13,599 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1406 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12193 hom.)
• Consequence: DKK2 NM_014421.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.67
• Publications: 42 publications found

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]

ENSG00000286147 (HGNC:58864):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002414912).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014421.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKK2	NM_014421.3	MANE Select	c.437G>A	p.Arg146Gln	missense	Exon 3 of 4	NP_055236.1	Q9UBU2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKK2	ENST00000285311.8	TSL:1 MANE Select	c.437G>A	p.Arg146Gln	missense	Exon 3 of 4	ENSP00000285311.3	Q9UBU2
	DKK2	ENST00000513208.5	TSL:1	c.137G>A	p.Arg46Gln	missense	Exon 4 of 5	ENSP00000421255.1	D6RGF1
	DKK2	ENST00000510534.1	TSL:1	n.658G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16302 AN: 151934 Hom.: 1405 Cov.: 32

Gnomad AFR AF: 0.0277

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.146 AC: 36776 AN: 251264 AF XY: 0.140

Gnomad AFR exome AF: 0.0275

Gnomad AMR exome AF: 0.290

Gnomad ASJ exome AF: 0.0639

Gnomad EAS exome AF: 0.385

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.115 AC: 168205 AN: 1461448 Hom.: 12193 Cov.: 32 AF XY: 0.114 AC XY: 82784 AN XY: 727034

African (AFR) AF: 0.0218 AC: 728 AN: 33462

American (AMR) AF: 0.288 AC: 12865 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0643 AC: 1679 AN: 26122

East Asian (EAS) AF: 0.351 AC: 13904 AN: 39668

South Asian (SAS) AF: 0.120 AC: 10312 AN: 86240

European-Finnish (FIN) AF: 0.123 AC: 6592 AN: 53414

Middle Eastern (MID) AF: 0.0807 AC: 465 AN: 5764

European-Non Finnish (NFE) AF: 0.103 AC: 114209 AN: 1111712

Other (OTH) AF: 0.123 AC: 7451 AN: 60374

GnomAD4 genome AF: 0.107 AC: 16311 AN: 152052 Hom.: 1406 Cov.: 32 AF XY: 0.114 AC XY: 8437 AN XY: 74314

African (AFR) AF: 0.0276 AC: 1144 AN: 41494

American (AMR) AF: 0.236 AC: 3595 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 200 AN: 3470

East Asian (EAS) AF: 0.388 AC: 1999 AN: 5152

South Asian (SAS) AF: 0.128 AC: 617 AN: 4820

European-Finnish (FIN) AF: 0.128 AC: 1349 AN: 10554

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6933 AN: 67986

Other (OTH) AF: 0.114 AC: 240 AN: 2112

Alfa AF: 0.105 Hom.: 3722

Bravo AF: 0.115

TwinsUK AF: 0.0963 AC: 357

ALSPAC AF: 0.106 AC: 407

ESP6500AA AF: 0.0320 AC: 141

ESP6500EA AF: 0.102 AC: 881

ExAC AF: 0.137 AC: 16572

Asia WGS AF: 0.262 AC: 909 AN: 3478

EpiCase AF: 0.0984

EpiControl AF: 0.0984

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.18
Sift	Benign	0.38	T
Sift4G	Benign	0.61	T
Polyphen		0.99	D
Vest4		0.060
MPC		0.80
ClinPred		0.017	T
GERP RS		5.8
Varity_R		0.15
gMVP		0.79
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17037102; hg19: chr4-107845794; COSMIC: COSV53394954;