4-106924637-C-T

Position:

• chr4-106924637-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DKK2	NM_014421.3	c.437G>A	p.Arg146Gln	missense_variant	3/4	ENST00000285311.8	NP_055236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DKK2	ENST00000285311.8	c.437G>A	p.Arg146Gln	missense_variant	3/4	1	NM_014421.3	ENSP00000285311	P1
	ENST00000650850.1	n.931+4449C>T		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.146 AC: 36776 AN: 251264 Hom.: 3984 AF XY: 0.140 AC XY: 19042 AN XY: 135782

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 SAS exome AF: 0.117

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

Gnomad4 AFR exome AF: 0.0218

Gnomad4 AMR exome AF: 0.288

Gnomad4 ASJ exome AF: 0.0643

Gnomad4 EAS exome AF: 0.351

Gnomad4 SAS exome AF: 0.120

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.103

Gnomad4 OTH exome AF: 0.123

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

Gnomad4 AFR AF: 0.0276

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.0576

Gnomad4 EAS AF: 0.388

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.114

Alfa AF: 0.105 Hom.: 2651

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 v4.3

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;D;D
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	0.066	P;P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.090	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.61	T;T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs17037102; hg19: chr4-107845794; COSMIC: COSV53394954;