rs34192549

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004431.5(EPHA2):c.1171G>A(p.Gly391Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,614,014 control chromosomes in the GnomAD database, including 509 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 55 hom., cov: 32)

Exomes 𝑓: 0.018 ( 454 hom. )

Consequence

EPHA2
NM_004431.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0730

Publications

40 publications found

Variant links:

Genes affected

EPHA2 (HGNC:3386): (EPH receptor A2) This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. This gene encodes a protein that binds ephrin-A ligands. Mutations in this gene are the cause of certain genetically-related cataract disorders.[provided by RefSeq, May 2010]

EPHA2 Gene-Disease associations (from GenCC):

cataract 6 multiple types
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
early-onset non-syndromic cataract
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset posterior polar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset posterior subcapsular cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
total early-onset cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

EPHA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030229986).

BP6

Variant 1-16137994-C-T is Benign according to our data. Variant chr1-16137994-C-T is described in ClinVar as Benign. ClinVar VariationId is 259386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0623 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004431.5. 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
	EPHA2	NM_004431.5	MANE Select	c.1171G>A	p.Gly391Arg	missense	Exon 5 of 17	NP_004422.2
	EPHA2	NM_001329090.2		c.1009G>A	p.Gly337Arg	missense	Exon 4 of 16	NP_001316019.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPHA2	ENST00000358432.8	TSL:1 MANE Select	c.1171G>A	p.Gly391Arg	missense	Exon 5 of 17	ENSP00000351209.5	P29317-1
EPHA2	ENST00000917106.1		c.1171G>A	p.Gly391Arg	missense	Exon 5 of 17	ENSP00000587165.1
EPHA2	ENST00000863593.1		c.1171G>A	p.Gly391Arg	missense	Exon 5 of 17	ENSP00000533652.1

Frequencies

GnomAD3 genomes

AF:

0.0166

AC:

2531

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00393

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0656

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.00809

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0170

Gnomad OTH

AF:

0.0186

GnomAD2 exomes

AF:

0.0246

AC:

6175

AN:

250856

AF XY:

0.0223

show subpopulations

Gnomad AFR exome

AF:

0.00376

Gnomad AMR exome

AF:

0.102

Gnomad ASJ exome

AF:

0.00427

Gnomad EAS exome

AF:

0.00114

Gnomad FIN exome

AF:

0.00952

Gnomad NFE exome

AF:

0.0151

Gnomad OTH exome

AF:

0.0208

GnomAD4 exome

AF:

0.0177

AC:

25847

AN:

1461658

Hom.:

454

Cov.:

AF XY:

0.0174

AC XY:

12687

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.00293

AC:

AN:

33480

American (AMR)

AF:

0.0969

AC:

4330

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00360

AC:

AN:

26136

East Asian (EAS)

AF:

0.000630

AC:

AN:

39696

South Asian (SAS)

AF:

0.0149

AC:

1281

AN:

86256

European-Finnish (FIN)

AF:

0.00960

AC:

511

AN:

53242

Middle Eastern (MID)

AF:

0.00538

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0168

AC:

18653

AN:

1111998

Other (OTH)

AF:

0.0136

AC:

824

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1986

3972

5959

7945

9931

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

758

1516

2274

3032

3790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0166

AC:

2533

AN:

152356

Hom.:

Cov.:

AF XY:

0.0165

AC XY:

1232

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00392

AC:

163

AN:

41584

American (AMR)

AF:

0.0657

AC:

1005

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3468

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.0145

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00809

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0170

AC:

1156

AN:

68034

Other (OTH)

AF:

0.0184

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

132

265

397

530

662

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0164

Hom.:

102

Bravo

AF:

0.0202

TwinsUK

AF:

0.0140

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0173

AC:

149

ExAC

AF:

0.0209

AC:

2541

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0142

EpiControl

AF:

0.0142

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cataract 6 multiple types (3)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.54

CADD

Benign

8.2

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.31

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.15

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.2

PhyloP100

0.073

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.12

Sift

Uncertain

0.017

Sift4G

Benign

0.073

Polyphen

0.0010

Vest4

0.088

MutPred

0.30

Gain of solvent accessibility (P = 0.0456)

MPC

0.16

ClinPred

0.026

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.26

gMVP

0.51

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over