chr17-7225870-T-A

Position:

• chr17-7225870-T-A

Variant summary

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

The NM_004422.3(DVL2):​c.2206A>T​(p.Met736Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 7.49

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DVL2	NM_004422.3	c.2206A>T	p.Met736Leu	missense_variant	15/15	ENST00000005340.10
DVL2	XM_005256502.3	c.2194A>T	p.Met732Leu	missense_variant	15/15
DVL2	XM_047435518.1	c.1900A>T	p.Met634Leu	missense_variant	15/15
DVL2	XM_047435522.1	c.1426A>T	p.Met476Leu	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DVL2	ENST00000005340.10	c.2206A>T	p.Met736Leu	missense_variant	15/15	1	NM_004422.3	P2
DVL2	ENST00000575458.5	c.2188A>T	p.Met730Leu	missense_variant	15/15	2		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Dec 09, 2023

The c.2206A>T (p.M736L) alteration is located in exon 15 (coding exon 15) of the DVL2 gene. This alteration results from a A to T substitution at nucleotide position 2206, causing the methionine (M) at amino acid position 736 to be replaced by a leucine (L). 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	0.70
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Uncertain	0.62	D;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.2	N;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.011	D;.
Sift4G	Uncertain	0.020	D;D
Polyphen		0.52	P;.
Vest4		0.63
MutPred		0.51		Gain of relative solvent accessibility (P = 0.0023);.;
MVP		0.50
MPC		0.20
ClinPred		0.90	D
GERP RS		5.3
Varity_R		0.56
gMVP		0.45

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: chr17-7129189;