chr6-168307583-G-A

Variant names:

• chr6-168307583-G-A
• rs761233827
• NM_214462.5:c.2174C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_214462.5(DACT2):​c.2174C>T​(p.Ala725Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000478 in 1,549,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. A725E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: DACT2 NM_214462.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.452
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035142392).

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.2174C>T	p.Ala725Val	missense	Exon 4 of 4	NP_999627.2	Q5SW24-1
	DACT2	NM_001286350.2		c.1664C>T	p.Ala555Val	missense	Exon 3 of 3	NP_001273279.1	Q5SW24-2
	DACT2	NM_001286351.2		c.658+2585C>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.2174C>T	p.Ala725Val	missense	Exon 4 of 4	ENSP00000355760.3	Q5SW24-1
	DACT2	ENST00000610183.1	TSL:1	c.1664C>T	p.Ala555Val	missense	Exon 3 of 3	ENSP00000476573.1	Q5SW24-2
	DACT2	ENST00000607983.1	TSL:1	c.950C>T	p.Ala317Val	missense	Exon 2 of 2	ENSP00000476434.1	Q5SW24-3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000658 AC: 10 AN: 151970 AF XY: 0.0000992

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000172

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000508 AC: 71 AN: 1397638 Hom.: 0 Cov.: 36 AF XY: 0.0000595 AC XY: 41 AN XY: 689252

African (AFR) AF: 0.00 AC: 0 AN: 31526

American (AMR) AF: 0.00 AC: 0 AN: 35500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25056

East Asian (EAS) AF: 0.000420 AC: 15 AN: 35710

South Asian (SAS) AF: 0.000291 AC: 23 AN: 79072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.0000278 AC: 30 AN: 1078300

Other (OTH) AF: 0.0000518 AC: 3 AN: 57902

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74266

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5156

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000790 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.083
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.8
DANN	Benign	0.86
DEOGEN2	Benign	0.042	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.45
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.030
Sift	Benign	0.34	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.062
MutPred		0.38		Loss of sheet (P = 0.0084)
MVP		0.014
ClinPred		0.92	D
GERP RS		0.76
Varity_R		0.027
gMVP		0.12
Mutation Taster		=99/1	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: rs761233827; hg19: chr6-168708263;