rs2291804

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.824-11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,613,248 control chromosomes in the GnomAD database, including 524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 41 hom., cov: 33)

Exomes 𝑓: 0.023 ( 483 hom. )

Consequence

EPHA2
NM_004431.5 intron

Scores

Splicing: ADA: 0.006032

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0490

Publications

3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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 (BayesDel_noAF=-0.74).

BP6

Variant 1-16138441-C-T is Benign according to our data. Variant chr1-16138441-C-T is described in ClinVar as [Benign]. Clinvar id is 259396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0184 (2799/152318) while in subpopulation SAS AF = 0.0476 (230/4828). AF 95% confidence interval is 0.0426. There are 41 homozygotes in GnomAd4. There are 1471 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 41 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA2	NM_004431.5 link	c.824-11G>A		intron_variant	Intron 3 of 16	ENST00000358432.8	NP_004422.2	P29317-1A0A024QZA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8 link	c.824-11G>A		intron_variant	Intron 3 of 16	1	NM_004431.5	ENSP00000351209.5		P29317-1
EPHA2	ENST00000480202.1 link	n.29-11G>A		intron_variant	Intron 1 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.0184

AC:

2806

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00381

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0112

Gnomad ASJ

AF:

0.0251

Gnomad EAS

AF:

0.0262

Gnomad SAS

AF:

0.0474

Gnomad FIN

AF:

0.0424

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0225

Gnomad OTH

AF:

0.0167

GnomAD2 exomes

AF:

0.0252

AC:

6272

AN:

248464

AF XY:

0.0263

show subpopulations

Gnomad AFR exome

AF:

0.00325

Gnomad AMR exome

AF:

0.00983

Gnomad ASJ exome

AF:

0.0231

Gnomad EAS exome

AF:

0.0282

Gnomad FIN exome

AF:

0.0425

Gnomad NFE exome

AF:

0.0229

Gnomad OTH exome

AF:

0.0299

GnomAD4 exome

AF:

0.0235

AC:

34276

AN:

1460930

Hom.:

483

Cov.:

AF XY:

0.0242

AC XY:

17609

AN XY:

726684

show subpopulations

African (AFR)

AF:

0.00326

AC:

109

AN:

33480

American (AMR)

AF:

0.00973

AC:

435

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0227

AC:

593

AN:

26134

East Asian (EAS)

AF:

0.0280

AC:

1113

AN:

39692

South Asian (SAS)

AF:

0.0457

AC:

3939

AN:

86236

European-Finnish (FIN)

AF:

0.0420

AC:

2206

AN:

52586

Middle Eastern (MID)

AF:

0.0293

AC:

169

AN:

5768

European-Non Finnish (NFE)

AF:

0.0218

AC:

24275

AN:

1111924

Other (OTH)

AF:

0.0238

AC:

1437

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

2022

4045

6067

8090

10112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

932

1864

2796

3728

4660

<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:

0.0184

AC:

2799

AN:

152318

Hom.:

Cov.:

AF XY:

0.0198

AC XY:

1471

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00380

AC:

158

AN:

41570

American (AMR)

AF:

0.0111

AC:

170

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0251

AC:

AN:

3472

East Asian (EAS)

AF:

0.0258

AC:

134

AN:

5186

South Asian (SAS)

AF:

0.0476

AC:

230

AN:

4828

European-Finnish (FIN)

AF:

0.0424

AC:

450

AN:

10614

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0225

AC:

1528

AN:

68018

Other (OTH)

AF:

0.0161

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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

114

152

190

<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:

0.0211

Hom.:

Bravo

AF:

0.0153

Asia WGS

AF:

0.0560

AC:

196

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 11, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28881807) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cataract 6 multiple types

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

8.0

(source)

DANN

Benign

0.69

PhyloP100

-0.049

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0060

dbscSNV1_RF

Benign

0.098

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over