2-176080418-C-T

Variant names:

• chr2-176080418-C-T
• rs1355876615
• NM_001080458.2:c.1120G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080458.2(EVX2):​c.1120G>A​(p.Ala374Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000834 in 1,079,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: EVX2 NM_001080458.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1941539).

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.1120G>A	p.Ala374Thr	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.1120G>A	p.Ala374Thr	missense	Exon 3 of 3	ENSP00000312385.4	Q03828

Frequencies

GnomAD3 genomes AF: 0.0000137 AC: 2 AN: 145592 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000305

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000573 AC: 1 AN: 1746 AF XY: 0.000852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000996

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000750 AC: 7 AN: 933772 Hom.: 0 Cov.: 32 AF XY: 0.00000683 AC XY: 3 AN XY: 439184

African (AFR) AF: 0.00 AC: 0 AN: 18370

American (AMR) AF: 0.00 AC: 0 AN: 4126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8048

East Asian (EAS) AF: 0.00 AC: 0 AN: 12086

South Asian (SAS) AF: 0.00 AC: 0 AN: 18910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2138

European-Non Finnish (NFE) AF: 0.00000847 AC: 7 AN: 826758

Other (OTH) AF: 0.00 AC: 0 AN: 33326

GnomAD4 genome AF: 0.0000137 AC: 2 AN: 145592 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 70822

African (AFR) AF: 0.00 AC: 0 AN: 40530

American (AMR) AF: 0.00 AC: 0 AN: 14784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3382

East Asian (EAS) AF: 0.00 AC: 0 AN: 4896

South Asian (SAS) AF: 0.00 AC: 0 AN: 4768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000305 AC: 2 AN: 65494

Other (OTH) AF: 0.00 AC: 0 AN: 2018

Alfa AF: 0.00 Hom.: 0

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	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.25
Sift	Benign	0.13	T
Sift4G	Benign	0.22	T
Polyphen		0.76	P
Vest4		0.21
MutPred		0.22		Gain of glycosylation at A374 (P = 0.0015)
MVP		0.85
ClinPred		0.056	T
GERP RS		3.7
Varity_R		0.10
gMVP		0.78
Mutation Taster		=91/9	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: rs1355876615; hg19: chr2-176945146;