NM_001080458.2:c.1410C>G

Variant names:

• chr2-176080128-G-C
• rs201835366
• NM_001080458.2:c.1410C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D470N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (16 hom.)
• Consequence: EVX2 NM_001080458.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0540
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 3034305.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080458.2. 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
	EVX2	NM_001080458.2	MANE Select	c.1410C>G	p.Asp470Glu	missense	Exon 3 of 3	NP_001073927.1	Q03828

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVX2	ENST00000308618.5	TSL:5 MANE Select	c.1410C>G	p.Asp470Glu	missense	Exon 3 of 3	ENSP00000312385.4	Q03828

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 428 AN: 151784 Hom.: 2 Cov.: 32

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

GnomAD2 exomes AF: 0.00215 AC: 360 AN: 167774 AF XY: 0.00218

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 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.: 16 Cov.: 31 AF XY: 0.00441 AC XY: 3058 AN XY: 693202

African (AFR) AF: 0.000656 AC: 19 AN: 28946

American (AMR) AF: 0.000804 AC: 30 AN: 37322

Ashkenazi Jewish (ASJ) AF: 0.000124 AC: 3 AN: 24184

East Asian (EAS) AF: 0.00 AC: 0 AN: 32742

South Asian (SAS) AF: 0.000240 AC: 19 AN: 79040

European-Finnish (FIN) AF: 0.00116 AC: 56 AN: 48470

Middle Eastern (MID) AF: 0.00165 AC: 7 AN: 4254

European-Non Finnish (NFE) AF: 0.00553 AC: 5989 AN: 1083474

Other (OTH) AF: 0.00332 AC: 190 AN: 57294

GnomAD4 genome AF: 0.00282 AC: 428 AN: 151892 Hom.: 2 Cov.: 32 AF XY: 0.00242 AC XY: 180 AN XY: 74242

African (AFR) AF: 0.00116 AC: 48 AN: 41496

American (AMR) AF: 0.00236 AC: 36 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4800

European-Finnish (FIN) AF: 0.000568 AC: 6 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00479 AC: 325 AN: 67878

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00300 Hom.: 2

Bravo AF: 0.00288

ESP6500AA AF: 0.00117 AC: 5

ESP6500EA AF: 0.00346 AC: 29

ExAC AF: 0.00214 AC: 254

Asia WGS AF: 0.000870 AC: 3 AN: 3464

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	EVX2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-0.054
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.25
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.052
MutPred		0.076		Gain of glycosylation at P473 (P = 0.1336)
MVP		0.52
ClinPred		0.021	T
GERP RS		0.75
Varity_R		0.10
gMVP		0.081
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs201835366; hg19: chr2-176944856; COSMIC: COSV57963131;