chr6-168307787-G-A

Variant names:

• chr6-168307787-G-A
• rs779905976
• NM_214462.5:c.1970C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T657N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: DACT2 NM_214462.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085693866).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_214462.5. 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
	DACT2	NM_214462.5	MANE Select	c.1970C>T	p.Thr657Ile	missense	Exon 4 of 4	NP_999627.2	Q5SW24-1
	DACT2	NM_001286350.2		c.1460C>T	p.Thr487Ile	missense	Exon 3 of 3	NP_001273279.1	Q5SW24-2
	DACT2	NM_001286351.2		c.658+2381C>T		intron	N/A	NP_001273280.1	Q5SW24-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DACT2	ENST00000366795.4	TSL:2 MANE Select	c.1970C>T	p.Thr657Ile	missense	Exon 4 of 4	ENSP00000355760.3	Q5SW24-1
	DACT2	ENST00000610183.1	TSL:1	c.1460C>T	p.Thr487Ile	missense	Exon 3 of 3	ENSP00000476573.1	Q5SW24-2
	DACT2	ENST00000607983.1	TSL:1	c.746C>T	p.Thr249Ile	missense	Exon 2 of 2	ENSP00000476434.1	Q5SW24-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1392126 Hom.: 0 Cov.: 38 AF XY: 0.00000437 AC XY: 3 AN XY: 686926

African (AFR) AF: 0.00 AC: 0 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 35666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.00 AC: 0 AN: 35720

South Asian (SAS) AF: 0.00 AC: 0 AN: 79188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078504

Other (OTH) AF: 0.00 AC: 0 AN: 57932

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	13
DANN	Benign	0.71
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.016
Sift	Benign	0.17	T
Sift4G	Benign	0.19	T
Polyphen		0.063	B
Vest4		0.037
MutPred		0.36		Loss of phosphorylation at T657 (P = 0.0056)
MVP		0.040
ClinPred		0.14	T
GERP RS		2.7
Varity_R		0.033
gMVP		0.098
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs779905976; hg19: chr6-168708467;