Genetic Variant DACT2:p.Ala721Glu (chr6-168307595-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_214462.5(DACT2):c.2162C>A(p.Ala721Glu) 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 1,397,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. A721V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DACT2
NM_214462.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.196

Publications

0 publications found

Variant links:

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]

DACT2 links:

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ACMG classification

Classification was made for transcript

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=0.034710318).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DACT2	NM_214462.5	MANE Select	c.2162C>A	p.Ala721Glu	missense	Exon 4 of 4	NP_999627.2	Q5SW24-1
DACT2	NM_001286350.2		c.1652C>A	p.Ala551Glu	missense	Exon 3 of 3	NP_001273279.1	Q5SW24-2
DACT2	NM_001286351.2		c.658+2573C>A		intron	N/A	NP_001273280.1	Q5SW24-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DACT2	ENST00000366795.4	TSL:2 MANE Select	c.2162C>A	p.Ala721Glu	missense	Exon 4 of 4	ENSP00000355760.3	Q5SW24-1
DACT2	ENST00000610183.1	TSL:1	c.1652C>A	p.Ala551Glu	missense	Exon 3 of 3	ENSP00000476573.1	Q5SW24-2
DACT2	ENST00000607983.1	TSL:1	c.938C>A	p.Ala313Glu	missense	Exon 2 of 2	ENSP00000476434.1	Q5SW24-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000215

AC:

AN:

1397030

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

688882

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31516

American (AMR)

AF:

0.00

AC:

AN:

35446

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25004

East Asian (EAS)

AF:

0.00

AC:

AN:

35698

South Asian (SAS)

AF:

0.00

AC:

AN:

78960

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48904

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.00000278

AC:

AN:

1077942

Other (OTH)

AF:

0.00

AC:

AN:

57882

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.026

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.038

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0098

LIST_S2

Benign

0.34

M_CAP

Benign

0.031

MetaRNN

Benign

0.035

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.14

PhyloP100

0.20

PrimateAI

Benign

0.47

PROVEAN

Benign

0.67

REVEL

Benign

0.13

Sift

Benign

0.96

Sift4G

Benign

0.88

Polyphen

0.019

Vest4

0.14

MutPred

0.29

Gain of disorder (P = 0.0586)

MVP

0.014

ClinPred

0.043

GERP RS

-6.7

Varity_R

0.061

gMVP

0.062

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over