6-168307707-C-T

Variant names:

• chr6-168307707-C-T
• rs1260662442
• NM_214462.5:c.2050G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_214462.5(DACT2):​c.2050G>A​(p.Gly684Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,398,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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: 0.0000014 (0 hom.)
• Consequence: DACT2 NM_214462.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.91

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 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=0.2202326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DACT2	NM_214462.5	c.2050G>A	p.Gly684Arg	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.2050G>A	p.Gly684Arg	missense_variant	Exon 4 of 4	2	NM_214462.5	ENSP00000355760.3
DACT2	ENST00000610183.1	c.1540G>A	p.Gly514Arg	missense_variant	Exon 3 of 3	1		ENSP00000476573.1
DACT2	ENST00000607983.1	c.826G>A	p.Gly276Arg	missense_variant	Exon 2 of 2	1		ENSP00000476434.1
DACT2	ENST00000366796.7	c.658+2461G>A		intron_variant	Intron 3 of 5	1		ENSP00000355761.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398034 Hom.: 0 Cov.: 37 AF XY: 0.00000145 AC XY: 1 AN XY: 689614

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: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2050G>A (p.G684R) 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 2050, causing the glycine (G) at amino acid position 684 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	0.19
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	N;.;.
REVEL	Benign	0.25
Sift	Uncertain	0.029	D;.;.
Sift4G	Benign	0.071	T;D;T
Polyphen		0.99	D;.;.
Vest4		0.10
MutPred		0.17		Gain of solvent accessibility (P = 0.0971);.;.;
MVP		0.16
ClinPred		0.92	D
GERP RS		4.5
Varity_R		0.18
gMVP		0.21

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: rs1260662442; hg19: chr6-168708387;