rs116506614

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS1

The NM_004431.5(EPHA2):c.2162G>A(p.Arg721Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0012 in 1,614,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 0 hom. )

Consequence

EPHA2
NM_004431.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:1

Conservation

PhyloP100: 6.16

Publications

24 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: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 1-16132227-C-T is Benign according to our data. Variant chr1-16132227-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13262.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000689 (105/152332) while in subpopulation NFE AF = 0.0011 (75/68022). AF 95% confidence interval is 0.000902. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2162G>A	p.Arg721Gln	missense	Exon 13 of 17	NP_004422.2
	EPHA2	NM_001329090.2		c.2000G>A	p.Arg667Gln	missense	Exon 12 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.2162G>A	p.Arg721Gln	missense	Exon 13 of 17	ENSP00000351209.5	P29317-1
EPHA2	ENST00000917106.1		c.2162G>A	p.Arg721Gln	missense	Exon 13 of 17	ENSP00000587165.1
EPHA2	ENST00000863593.1		c.2162G>A	p.Arg721Gln	missense	Exon 13 of 17	ENSP00000533652.1

Frequencies

GnomAD3 genomes

AF:

0.000690

AC:

105

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000736

AC:

185

AN:

251218

AF XY:

0.000560

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00125

AC:

1830

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

871

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33480

American (AMR)

AF:

0.00127

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00151

AC:

1676

AN:

1112004

Other (OTH)

AF:

0.00123

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

129

258

387

516

645

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

132

198

264

330

<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:

0.000689

AC:

105

AN:

152332

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41564

American (AMR)

AF:

0.000457

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00110

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000755

Hom.:

Bravo

AF:

0.000850

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000593

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.00148

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cataract 6 multiple types (2)

Cataract 6, age-related cortical (1)

EPHA2-related disorder (1)

Meniere disease (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.044

MetaRNN

Uncertain

0.44

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.2

PhyloP100

6.2

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.46

Sift

Benign

0.12

Sift4G

Benign

0.089

Polyphen

1.0

Vest4

0.95

MVP

0.88

MPC

1.7

ClinPred

0.064

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.83

Mutation Taster

=26/74

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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