Genetic Variant NM_004422.3:c.1586G>C (chr17-7226597-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004422.3(DVL2):c.1586G>C(p.Gly529Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,440,090 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G529E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DVL2
NM_004422.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.57

Publications

0 publications found

Variant links:

Genes affected

DVL2 (HGNC:3086): (dishevelled segment polarity protein 2) This gene encodes a member of the dishevelled (dsh) protein family. The vertebrate dsh proteins have approximately 40% amino acid sequence similarity with Drosophila dsh. This gene encodes a 90-kD protein that undergoes posttranslational phosphorylation to form a 95-kD cytoplasmic protein, which may play a role in the signal transduction pathway mediated by multiple Wnt proteins. The mechanisms of dishevelled function in Wnt signaling are likely to be conserved among metazoans. [provided by RefSeq, Jul 2008]

DVL2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004422.3. 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
	DVL2	NM_004422.3	MANE Select	c.1586G>C	p.Gly529Ala	missense	Exon 14 of 15	NP_004413.1	O14641

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DVL2	ENST00000005340.10	TSL:1 MANE Select	c.1586G>C	p.Gly529Ala	missense	Exon 14 of 15	ENSP00000005340.4	O14641
DVL2	ENST00000951245.1		c.1652G>C	p.Gly551Ala	missense	Exon 14 of 15	ENSP00000621304.1
DVL2	ENST00000930220.1		c.1640G>C	p.Gly547Ala	missense	Exon 14 of 15	ENSP00000600279.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1440090

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

716030

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32388

American (AMR)

AF:

0.00

AC:

AN:

39966

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24810

East Asian (EAS)

AF:

0.00

AC:

AN:

39272

South Asian (SAS)

AF:

0.00

AC:

AN:

83752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51458

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5592

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1103452

Other (OTH)

AF:

0.00

AC:

AN:

59400

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Uncertain

0.41

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

PhyloP100

7.6

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.28

Sift

Benign

0.064

Sift4G

Benign

0.17

Polyphen

0.97

Vest4

0.77

MutPred

0.15

Loss of glycosylation at S528 (P = 0.0737)

MVP

0.72

MPC

0.84

ClinPred

0.96

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.40

Mutation Taster

=65/35

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