2-176080234-G-C

Variant names:

• chr2-176080234-G-C
• rs1689114753
• NM_001080458.2:c.1304C>G

Variant summary

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

The NM_001080458.2(EVX2):​c.1304C>G​(p.Ser435Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000791 in 1,264,048 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S435L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: EVX2 NM_001080458.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.86
• 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 2 ACMG points.

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

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.1304C>G	p.Ser435Trp	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.1304C>G	p.Ser435Trp	missense	Exon 3 of 3	ENSP00000312385.4	Q03828

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.91e-7 AC: 1 AN: 1264048 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 622608

African (AFR) AF: 0.00 AC: 0 AN: 26212

American (AMR) AF: 0.00 AC: 0 AN: 24066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21634

East Asian (EAS) AF: 0.00 AC: 0 AN: 27398

South Asian (SAS) AF: 0.00 AC: 0 AN: 65236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3640

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1012362

Other (OTH) AF: 0.0000195 AC: 1 AN: 51214

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.6	L
PhyloP100		5.9
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.34		Loss of glycosylation at S435 (P = 9e-04)
MVP		0.87
ClinPred		0.90	D
GERP RS		2.8
Varity_R		0.31
gMVP		0.60
Mutation Taster		=57/43	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: rs1689114753; hg19: chr2-176944962;