Genetic Variant DACT2:p.Glu669Lys (chr6-168307752-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_214462.5(DACT2):c.2005G>A(p.Glu669Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000349 in 1,547,752 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

DACT2
NM_214462.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.21

Variant links:

Genes affected

DACT2 (HGNC:21231): (dishevelled binding antagonist of beta catenin 2) Predicted to enable several functions, including beta-catenin binding activity; delta-catenin binding activity; and protein kinase C binding activity. Predicted to be involved in several processes, including epithelial cell morphogenesis; inner medullary collecting duct development; and negative regulation of nodal signaling pathway. Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DACT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27646118).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DACT2	NM_214462.5 link	c.2005G>A	p.Glu669Lys	missense_variant	Exon 4 of 4	ENST00000366795.4	NP_999627.2	Q5SW24-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DACT2	ENST00000366795.4 link	c.2005G>A	p.Glu669Lys	missense_variant	Exon 4 of 4	2	NM_214462.5	ENSP00000355760.3	Q5SW24-1
DACT2	ENST00000610183.1 link	c.1495G>A	p.Glu499Lys	missense_variant	Exon 3 of 3	1		ENSP00000476573.1	Q5SW24-2
DACT2	ENST00000607983.1 link	c.781G>A	p.Glu261Lys	missense_variant	Exon 2 of 2	1		ENSP00000476434.1	Q5SW24-3
DACT2	ENST00000366796.7 link	c.658+2416G>A		intron_variant	Intron 3 of 5	1		ENSP00000355761.2	Q5SW24-4

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000528

AC:

AN:

151650

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

80952

show subpopulations

Gnomad AFR exome

AF:

0.000256

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000440

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000841

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000330

AC:

AN:

1395592

Hom.:

Cov.:

AF XY:

0.0000363

AC XY:

AN XY:

688554

show subpopulations

Gnomad4 AFR exome

AF:

0.0000633

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0000379

Gnomad4 FIN exome

AF:

0.0000438

Gnomad4 NFE exome

AF:

0.0000324

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000411

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000314

AC:

ExAC

AF:

0.000111

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2005G>A (p.E669K) alteration is located in exon 4 (coding exon 4) of the DACT2 gene. This alteration results from a G to A substitution at nucleotide position 2005, causing the glutamic acid (E) at amino acid position 669 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;.;.

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.15

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.63

T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Uncertain

2.2

M;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.4

D;.;.

REVEL

Benign

0.24

Sift

Uncertain

0.0040

D;.;.

Sift4G

Uncertain

0.011

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.16

MVP

0.14

ClinPred

0.39

GERP RS

4.2

Varity_R

0.43

gMVP

0.39

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over