Genetic Variant EPHA2:p.Leu632Leu (chr1-16133337-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004431.5(EPHA2):c.1896G>A(p.Leu632Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00743 in 1,613,868 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0053 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0077 ( 51 hom. )

Consequence

EPHA2
NM_004431.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.65

Publications

4 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 1-16133337-C-T is Benign according to our data. Variant chr1-16133337-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 293419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.65 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00527 (803/152266) while in subpopulation AMR AF = 0.0083 (127/15302). AF 95% confidence interval is 0.0072. There are 2 homozygotes in GnomAd4. There are 382 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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.1896G>A	p.Leu632Leu	synonymous	Exon 11 of 17	NP_004422.2
	EPHA2	NM_001329090.2		c.1734G>A	p.Leu578Leu	synonymous	Exon 10 of 16	NP_001316019.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EPHA2	ENST00000358432.8	TSL:1 MANE Select	c.1896G>A	p.Leu632Leu	synonymous	Exon 11 of 17	ENSP00000351209.5
EPHA2	ENST00000917106.1		c.1896G>A	p.Leu632Leu	synonymous	Exon 11 of 17	ENSP00000587165.1
EPHA2	ENST00000863593.1		c.1896G>A	p.Leu632Leu	synonymous	Exon 11 of 17	ENSP00000533652.1

Frequencies

GnomAD3 genomes

AF:

0.00528

AC:

804

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00186

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00838

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.000564

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00775

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00561

AC:

1410

AN:

251242

AF XY:

0.00571

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00645

Gnomad ASJ exome

AF:

0.0113

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00798

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.00766

AC:

11189

AN:

1461602

Hom.:

Cov.:

AF XY:

0.00751

AC XY:

5458

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.00158

AC:

AN:

33480

American (AMR)

AF:

0.00725

AC:

324

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

264

AN:

26128

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00196

AC:

169

AN:

86258

European-Finnish (FIN)

AF:

0.00143

AC:

AN:

53216

Middle Eastern (MID)

AF:

0.0128

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00875

AC:

9725

AN:

1111956

Other (OTH)

AF:

0.00830

AC:

501

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

856

1712

2567

3423

4279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

366

732

1098

1464

1830

<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:

0.00527

AC:

803

AN:

152266

Hom.:

Cov.:

AF XY:

0.00513

AC XY:

382

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

41520

American (AMR)

AF:

0.00830

AC:

127

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00331

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000564

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00775

AC:

527

AN:

68006

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

142

189

236

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00791

Hom.:

Bravo

AF:

0.00589

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0101

EpiControl

AF:

0.00925

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Cataract 6 multiple types (2)

EPHA2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

6.4

(source)

DANN

Benign

0.68

PhyloP100

2.6

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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