NM_004422.3:c.1814G>C

Variant names:

• chr17-7226262-C-G
• rs781121098
• NM_004422.3:c.1814G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004422.3(DVL2):​c.1814G>C​(p.Gly605Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,604,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DVL2 NM_004422.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.597
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09383932).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

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.1814G>C	p.Gly605Ala	missense	Exon 15 of 15	NP_004413.1	O14641

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DVL2	ENST00000005340.10	TSL:1 MANE Select	c.1814G>C	p.Gly605Ala	missense	Exon 15 of 15	ENSP00000005340.4	O14641
	DVL2	ENST00000951245.1		c.1880G>C	p.Gly627Ala	missense	Exon 15 of 15	ENSP00000621304.1
	DVL2	ENST00000930220.1		c.1868G>C	p.Gly623Ala	missense	Exon 15 of 15	ENSP00000600279.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000171 AC: 4 AN: 233826 AF XY: 0.00000780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000226

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1452104 Hom.: 0 Cov.: 31 AF XY: 0.00000415 AC XY: 3 AN XY: 722302

African (AFR) AF: 0.00 AC: 0 AN: 33186

American (AMR) AF: 0.00 AC: 0 AN: 43394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25540

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 85412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108272

Other (OTH) AF: 0.00 AC: 0 AN: 60026

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.60
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.031
Sift	Benign	0.42	T
Sift4G	Benign	0.83	T
Polyphen		0.39	B
Vest4		0.15
MutPred		0.20		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.55
MPC		0.79
ClinPred		0.073	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.053
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs781121098; hg19: chr17-7129581;