17-7226597-C-T

Variant names:

• chr17-7226597-C-T
• rs1179132425
• NM_004422.3:c.1586G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004422.3(DVL2):​c.1586G>A​(p.Gly529Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,440,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DVL2 NM_004422.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DVL2	NM_004422.3	c.1586G>A	p.Gly529Glu	missense_variant	Exon 14 of 15	ENST00000005340.10	NP_004413.1
DVL2	XM_005256502.3	c.1574G>A	p.Gly525Glu	missense_variant	Exon 14 of 15		XP_005256559.1
DVL2	XM_047435518.1	c.1280G>A	p.Gly427Glu	missense_variant	Exon 14 of 15		XP_047291474.1
DVL2	XM_047435522.1	c.806G>A	p.Gly269Glu	missense_variant	Exon 9 of 10		XP_047291478.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DVL2	ENST00000005340.10	c.1586G>A	p.Gly529Glu	missense_variant	Exon 14 of 15	1	NM_004422.3	ENSP00000005340.4
DVL2	ENST00000575458.5	c.1568G>A	p.Gly523Glu	missense_variant	Exon 14 of 15	2		ENSP00000459797.1
DVL2	ENST00000575086.1	c.545G>A	p.Gly182Glu	missense_variant	Exon 6 of 7	3		ENSP00000458465.1
DVL2	ENST00000576840.5	n.*59G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1440090 Hom.: 0 Cov.: 36 AF XY: 0.00000140 AC XY: 1 AN XY: 716030

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: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1586G>A (p.G529E) alteration is located in exon 14 (coding exon 14) of the DVL2 gene. This alteration results from a G to A substitution at nucleotide position 1586, causing the glycine (G) at amino acid position 529 to be replaced by a glutamic acid (E). 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	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.9	D;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0070	D;.
Sift4G	Benign	0.13	T;T
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.18		Gain of solvent accessibility (P = 0.0456);.;
MVP		0.74
MPC		0.93
ClinPred		0.98	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1179132425; hg19: chr17-7129916;