17-7226250-T-C

Position:

• chr17-7226250-T-C

Variant summary

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

The NM_004422.3(DVL2):​c.1826A>G​(p.Glu609Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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)
• Consequence: DVL2 NM_004422.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.09

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16115001).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DVL2	NM_004422.3	c.1826A>G	p.Glu609Gly	missense_variant	15/15	ENST00000005340.10	NP_004413.1
DVL2	XM_005256502.3	c.1814A>G	p.Glu605Gly	missense_variant	15/15		XP_005256559.1
DVL2	XM_047435518.1	c.1520A>G	p.Glu507Gly	missense_variant	15/15		XP_047291474.1
DVL2	XM_047435522.1	c.1046A>G	p.Glu349Gly	missense_variant	10/10		XP_047291478.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DVL2	ENST00000005340.10	c.1826A>G	p.Glu609Gly	missense_variant	15/15	1	NM_004422.3	ENSP00000005340.4
DVL2	ENST00000575458.5	c.1808A>G	p.Glu603Gly	missense_variant	15/15	2		ENSP00000459797.1
DVL2	ENST00000575086.1	c.785A>G	p.Glu262Gly	missense_variant	7/7	3		ENSP00000458465.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

The c.1826A>G (p.E609G) alteration is located in exon 15 (coding exon 15) of the DVL2 gene. This alteration results from a A to G substitution at nucleotide position 1826, causing the glutamic acid (E) at amino acid position 609 to be replaced by a glycine (G). 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	0.069
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.029
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.0	N;.
REVEL	Benign	0.046
Sift	Benign	0.21	T;.
Sift4G	Benign	0.34	T;T
Polyphen		0.0	B;.
Vest4		0.23
MutPred		0.21		Gain of MoRF binding (P = 0.0194);.;
MVP		0.51
MPC		0.67
ClinPred		0.53	D
GERP RS		5.5
Varity_R		0.10
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7129569;