2-176080397-T-A

Variant names:

• chr2-176080397-T-A
• rs1477849960
• NM_001080458.2:c.1141A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001080458.2(EVX2):​c.1141A>T​(p.Ser381Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000177 in 1,074,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S381G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000029 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: EVX2 NM_001080458.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.98
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35842288).

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.1141A>T	p.Ser381Cys	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.1141A>T	p.Ser381Cys	missense	Exon 3 of 3	ENSP00000312385.4	Q03828

Frequencies

GnomAD3 genomes AF: 0.0000288 AC: 4 AN: 138932 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000104

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000160 AC: 15 AN: 935894 Hom.: 0 Cov.: 32 AF XY: 0.0000181 AC XY: 8 AN XY: 443134

African (AFR) AF: 0.00 AC: 0 AN: 17952

American (AMR) AF: 0.00 AC: 0 AN: 4352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8942

East Asian (EAS) AF: 0.00 AC: 0 AN: 11360

South Asian (SAS) AF: 0.00 AC: 0 AN: 22996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2142

European-Non Finnish (NFE) AF: 0.0000169 AC: 14 AN: 826172

Other (OTH) AF: 0.0000304 AC: 1 AN: 32922

GnomAD4 genome AF: 0.0000288 AC: 4 AN: 138932 Hom.: 0 Cov.: 30 AF XY: 0.0000445 AC XY: 3 AN XY: 67482

African (AFR) AF: 0.000104 AC: 4 AN: 38376

American (AMR) AF: 0.00 AC: 0 AN: 14286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3324

East Asian (EAS) AF: 0.00 AC: 0 AN: 4244

South Asian (SAS) AF: 0.00 AC: 0 AN: 4100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63612

Other (OTH) AF: 0.00 AC: 0 AN: 1976

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.012	D
MutationAssessor	Benign	0.69	N
PhyloP100		2.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.049	D
Polyphen		0.99	D
Vest4		0.17
MutPred		0.23		Loss of glycosylation at S381 (P = 0)
MVP		0.80
ClinPred		0.42	T
GERP RS		3.5
Varity_R		0.15
gMVP		0.64
Mutation Taster		=83/17	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: rs1477849960; hg19: chr2-176945125;