6-168307590-C-T

Variant names:

• chr6-168307590-C-T
• rs191740169
• NM_214462.5:c.2167G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_214462.5(DACT2):​c.2167G>A​(p.Gly723Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,549,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: DACT2 NM_214462.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.721

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029669166).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DACT2	NM_214462.5	c.2167G>A	p.Gly723Arg	missense_variant	Exon 4 of 4	ENST00000366795.4	NP_999627.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DACT2	ENST00000366795.4	c.2167G>A	p.Gly723Arg	missense_variant	Exon 4 of 4	2	NM_214462.5	ENSP00000355760.3
DACT2	ENST00000610183.1	c.1657G>A	p.Gly553Arg	missense_variant	Exon 3 of 3	1		ENSP00000476573.1
DACT2	ENST00000607983.1	c.943G>A	p.Gly315Arg	missense_variant	Exon 2 of 2	1		ENSP00000476434.1
DACT2	ENST00000366796.7	c.658+2578G>A		intron_variant	Intron 3 of 5	1		ENSP00000355761.2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000178 AC: 27 AN: 151710 Hom.: 0 AF XY: 0.000174 AC XY: 14 AN XY: 80548

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000533

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000185

Gnomad SAS exome AF: 0.0000444

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000103

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.0000966 AC: 135 AN: 1397402 Hom.: 0 Cov.: 37 AF XY: 0.000104 AC XY: 72 AN XY: 689104

Gnomad4 AFR exome AF: 0.000539

Gnomad4 AMR exome AF: 0.000507

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000640

Gnomad4 OTH exome AF: 0.000259

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74432

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.000208

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2167G>A (p.G723R) 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 2167, causing the glycine (G) at amino acid position 723 to be replaced by an arginine (R). 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	-0.54	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.4
DANN	Benign	0.80
DEOGEN2	Benign	0.045	T;.;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.46	T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.030	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.22	N;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.80	N;.;.
REVEL	Benign	0.072
Sift	Benign	0.40	T;.;.
Sift4G	Benign	0.52	T;T;T
Polyphen		0.82	P;.;.
Vest4		0.096
MutPred		0.39		Loss of sheet (P = 0.0181);.;.;
MVP		0.040
ClinPred		0.010	T
GERP RS		-0.92
Varity_R		0.047
gMVP		0.083

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

Other links and lift over

dbSNP: rs191740169; hg19: chr6-168708270; COSMIC: COSV105923940;