chr6-168307583-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_214462.5(DACT2):​c.2174C>G​(p.Ala725Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,397,640 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DACT2 NM_214462.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.452
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032139987).

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>G	p.Ala725Gly	missense	Exon 4 of 4	NP_999627.2	Q5SW24-1
	DACT2	NM_001286350.2		c.1664C>G	p.Ala555Gly	missense	Exon 3 of 3	NP_001273279.1	Q5SW24-2
	DACT2	NM_001286351.2		c.658+2585C>G		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>G	p.Ala725Gly	missense	Exon 4 of 4	ENSP00000355760.3	Q5SW24-1
	DACT2	ENST00000610183.1	TSL:1	c.1664C>G	p.Ala555Gly	missense	Exon 3 of 3	ENSP00000476573.1	Q5SW24-2
	DACT2	ENST00000607983.1	TSL:1	c.950C>G	p.Ala317Gly	missense	Exon 2 of 2	ENSP00000476434.1	Q5SW24-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1397640 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 689254

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: 0.00 AC: 0 AN: 35710

South Asian (SAS) AF: 0.00 AC: 0 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: 9.27e-7 AC: 1 AN: 1078300

Other (OTH) AF: 0.00 AC: 0 AN: 57904

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.050
DANN	Benign	0.31
DEOGEN2	Benign	0.039	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.45
PrimateAI	Benign	0.46	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.024
Sift	Benign	0.54	T
Sift4G	Benign	0.89	T
Polyphen		0.0	B
Vest4		0.039
MutPred		0.32		Gain of sheet (P = 0.0827)
MVP		0.014
ClinPred		0.025	T
GERP RS		0.76
Varity_R		0.029
gMVP		0.079
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;