NM_004431.5:c.2904G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004431.5(EPHA2):c.2904G>C(p.Gln968His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,613,984 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 12 hom. )

Consequence

EPHA2
NM_004431.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.361

Publications

5 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008738786).

BP6

Variant 1-16125242-C-G is Benign according to our data. Variant chr1-16125242-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 293406.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00172 (262/152290) while in subpopulation NFE AF = 0.00278 (189/68028). AF 95% confidence interval is 0.00245. There are 0 homozygotes in GnomAd4. There are 128 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 12 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.2904G>C	p.Gln968His	missense	Exon 17 of 17	NP_004422.2
	EPHA2	NM_001329090.2		c.2742G>C	p.Gln914His	missense	Exon 16 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.2904G>C	p.Gln968His	missense	Exon 17 of 17	ENSP00000351209.5	P29317-1
EPHA2	ENST00000917106.1		c.2919G>C	p.Gln973His	missense	Exon 17 of 17	ENSP00000587165.1
EPHA2	ENST00000863593.1		c.2883G>C	p.Gln961His	missense	Exon 17 of 17	ENSP00000533652.1

Frequencies

GnomAD3 genomes

AF:

0.00172

AC:

261

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00278

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00187

AC:

467

AN:

250282

AF XY:

0.00184

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.000811

Gnomad ASJ exome

AF:

0.00418

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000650

Gnomad NFE exome

AF:

0.00294

Gnomad OTH exome

AF:

0.00328

GnomAD4 exome

AF:

0.00248

AC:

3629

AN:

1461694

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

1776

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33480

American (AMR)

AF:

0.000760

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00459

AC:

120

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000986

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.000506

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00288

AC:

3206

AN:

1111972

Other (OTH)

AF:

0.00240

AC:

145

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

181

362

542

723

904

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<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:

0.00172

AC:

262

AN:

152290

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000626

AC:

AN:

41562

American (AMR)

AF:

0.000981

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000623

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00278

AC:

189

AN:

68028

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.00249

Hom.:

Bravo

AF:

0.00171

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00203

AC:

247

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00305

EpiControl

AF:

0.00326

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)

EPHA2-related disorder (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.82

M_CAP

Benign

0.036

MetaRNN

Benign

0.0087

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.3

PhyloP100

0.36

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.1

REVEL

Benign

0.18

Sift

Benign

0.082

Sift4G

Benign

0.11

Polyphen

0.031

Vest4

0.54

MutPred

0.73

Gain of ubiquitination at K966 (P = 0.0767)

MVP

0.77

MPC

0.62

ClinPred

0.018

GERP RS

-2.2

Varity_R

0.21

gMVP

0.90

Mutation Taster

=90/10

polymorphism

(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