dbSNP rs779905976: DACT2:p.Thr657Ile (chr6-168307787-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_214462.5(DACT2):c.1970C>T(p.Thr657Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,392,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

DACT2
NM_214462.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.76

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.085693866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DACT2	NM_214462.5 link	c.1970C>T	p.Thr657Ile	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.1970C>T	p.Thr657Ile	missense_variant	Exon 4 of 4	2	NM_214462.5	ENSP00000355760.3	Q5SW24-1
DACT2	ENST00000610183.1 link	c.1460C>T	p.Thr487Ile	missense_variant	Exon 3 of 3	1		ENSP00000476573.1	Q5SW24-2
DACT2	ENST00000607983.1 link	c.746C>T	p.Thr249Ile	missense_variant	Exon 2 of 2	1		ENSP00000476434.1	Q5SW24-3
DACT2	ENST00000366796.7 link	c.658+2381C>T		intron_variant	Intron 3 of 5	1		ENSP00000355761.2	Q5SW24-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000215

AC:

AN:

1392126

Hom.:

Cov.:

AF XY:

0.00000437

AC XY:

AN XY:

686926

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000278

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1970C>T (p.T657I) alteration is located in exon 4 (coding exon 4) of the DACT2 gene. This alteration results from a C to T substitution at nucleotide position 1970, causing the threonine (T) at amino acid position 657 to be replaced by an isoleucine (I). 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

0.13

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.073

T;.;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.46

T;T;T

M_CAP

Benign

0.0052

MetaRNN

Benign

0.086

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.010

N;.;.

REVEL

Benign

0.016

Sift

Benign

0.17

T;.;.

Sift4G

Benign

0.19

T;T;D

Polyphen

0.063

B;.;.

Vest4

0.037

MutPred

0.36

Loss of phosphorylation at T657 (P = 0.0056);.;.;

MVP

0.040

ClinPred

0.14

GERP RS

2.7

Varity_R

0.033

gMVP

0.098

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over