Genetic Variant EVX2:p.Asp470Glu (chr2-176080128-G-C) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001080458.2(EVX2):c.1410C>G(p.Asp470Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 1,547,618 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 16 hom. )

Consequence

EVX2
NM_001080458.2 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.0540

Variant links:

Genes affected

EVX2 (HGNC:3507): (even-skipped homeobox 2) This gene is located at the 5' end of the HOXD gene cluster on chromosome 2. The encoded protein is a homeobox transcription factor that is related to the protein encoded by the Drosophila even-skipped (eve) gene, a member of the pair-rule class of segmentation genes. A 117 kb microdeletion at the 5' end of the HOXD gene cluster, which includes this gene and the HOXD9-HOXD13 genes, causes synpolydactyly, a dominantly inherited disease resulting in limb malformation. [provided by RefSeq, Sep 2009]

EVX2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009071797).

BP6

Variant 2-176080128-G-C is Benign according to our data. Variant chr2-176080128-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3034305.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVX2	NM_001080458.2 link	c.1410C>G	p.Asp470Glu	missense_variant	Exon 3 of 3	ENST00000308618.5	NP_001073927.1	Q03828

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVX2	ENST00000308618.5 link	c.1410C>G	p.Asp470Glu	missense_variant	Exon 3 of 3	5	NM_001080458.2	ENSP00000312385.4		Q03828

Frequencies

GnomAD3 genomes

AF:

0.00282

AC:

428

AN:

151784

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.000568

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00479

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00215

AC:

360

AN:

167774

Hom.:

AF XY:

0.00218

AC XY:

205

AN XY:

94060

show subpopulations

Gnomad AFR exome

AF:

0.000840

Gnomad AMR exome

AF:

0.000734

Gnomad ASJ exome

AF:

0.000130

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000215

Gnomad FIN exome

AF:

0.000664

Gnomad NFE exome

AF:

0.00425

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00452

AC:

6313

AN:

1395726

Hom.:

Cov.:

AF XY:

0.00441

AC XY:

3058

AN XY:

693202

show subpopulations

Gnomad4 AFR exome

AF:

0.000656

Gnomad4 AMR exome

AF:

0.000804

Gnomad4 ASJ exome

AF:

0.000124

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000240

Gnomad4 FIN exome

AF:

0.00116

Gnomad4 NFE exome

AF:

0.00553

Gnomad4 OTH exome

AF:

0.00332

GnomAD4 genome

AF:

0.00282

AC:

428

AN:

151892

Hom.:

Cov.:

AF XY:

0.00242

AC XY:

180

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.00116

Gnomad4 AMR

AF:

0.00236

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000417

Gnomad4 FIN

AF:

0.000568

Gnomad4 NFE

AF:

0.00479

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00300

Hom.:

Bravo

AF:

0.00288

ESP6500AA

AF:

0.00117

AC:

ESP6500EA

AF:

0.00346

AC:

ExAC

AF:

0.00214

AC:

254

Asia WGS

AF:

0.000870

AC:

AN:

3464

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

EVX2-related disorder

Benign:1

Feb 15, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.072

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.72

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.62

M_CAP

Pathogenic

0.67

MetaRNN

Benign

0.0091

MetaSVM

Benign

-0.79

MutationAssessor

Benign

-1.2

PrimateAI

Uncertain

0.73

PROVEAN

Benign

1.0

REVEL

Benign

0.25

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.052

MutPred

0.076

Gain of glycosylation at P473 (P = 0.1336);

MVP

0.52

ClinPred

0.021

GERP RS

0.75

Varity_R

0.10

gMVP

0.081

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over