rs35903225

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004431.5(EPHA2):c.2627G>A(p.Arg876His) variant causes a missense change. The variant allele was found at a frequency of 0.0236 in 1,613,878 control chromosomes in the GnomAD database, including 560 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 33 hom., cov: 32)

Exomes 𝑓: 0.024 ( 527 hom. )

Consequence

EPHA2
NM_004431.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.78

Publications

22 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=0.007658243).

BP6

Variant 1-16130268-C-T is Benign according to our data. Variant chr1-16130268-C-T is described in ClinVar as Benign. ClinVar VariationId is 259391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0172 (2616/152272) while in subpopulation NFE AF = 0.0274 (1865/68012). AF 95% confidence interval is 0.0264. There are 33 homozygotes in GnomAd4. There are 1242 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 AD,AR gene

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.2627G>A	p.Arg876His	missense	Exon 15 of 17	NP_004422.2
	EPHA2	NM_001329090.2		c.2465G>A	p.Arg822His	missense	Exon 14 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.2627G>A	p.Arg876His	missense	Exon 15 of 17	ENSP00000351209.5	P29317-1
EPHA2	ENST00000917106.1		c.2627G>A	p.Arg876His	missense	Exon 15 of 17	ENSP00000587165.1
EPHA2	ENST00000863593.1		c.2627G>A	p.Arg876His	missense	Exon 15 of 17	ENSP00000533652.1

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2616

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00497

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0199

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00651

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0274

Gnomad OTH

AF:

0.0181

GnomAD2 exomes

AF:

0.0171

AC:

4304

AN:

251144

AF XY:

0.0169

show subpopulations

Gnomad AFR exome

AF:

0.00523

Gnomad AMR exome

AF:

0.0150

Gnomad ASJ exome

AF:

0.0191

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00772

Gnomad NFE exome

AF:

0.0266

Gnomad OTH exome

AF:

0.0237

GnomAD4 exome

AF:

0.0243

AC:

35459

AN:

1461606

Hom.:

527

Cov.:

AF XY:

0.0235

AC XY:

17090

AN XY:

727064

show subpopulations

African (AFR)

AF:

0.00448

AC:

150

AN:

33478

American (AMR)

AF:

0.0159

AC:

711

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0227

AC:

594

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.00559

AC:

482

AN:

86194

European-Finnish (FIN)

AF:

0.00972

AC:

519

AN:

53418

Middle Eastern (MID)

AF:

0.0184

AC:

106

AN:

5758

European-Non Finnish (NFE)

AF:

0.0284

AC:

31576

AN:

1111844

Other (OTH)

AF:

0.0218

AC:

1318

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

2195

4390

6585

8780

10975

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1206

2412

3618

4824

6030

<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:

0.0172

AC:

2616

AN:

152272

Hom.:

Cov.:

AF XY:

0.0167

AC XY:

1242

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00496

AC:

206

AN:

41568

American (AMR)

AF:

0.0199

AC:

304

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.00394

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00651

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0274

AC:

1865

AN:

68012

Other (OTH)

AF:

0.0180

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

145

289

434

578

723

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0246

Hom.:

153

Bravo

AF:

0.0183

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0267

AC:

103

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.0256

AC:

220

ExAC

AF:

0.0169

AC:

2054

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0290

EpiControl

AF:

0.0279

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

0.31

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0077

MetaSVM

Benign

-0.36

MutationAssessor

Pathogenic

3.0

PhyloP100

4.8

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.27

Sift

Uncertain

0.026

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.14

MPC

1.6

ClinPred

0.052

GERP RS

5.6

Varity_R

0.60

gMVP

0.68

Mutation Taster

=78/22

polymorphism (auto)

(source)

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

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