rs2230597

Variant names:

• chr1-16138178-G-A
• rs2230597
• NM_004431.5:c.987C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004431.5(EPHA2):​c.987C>T​(p.Pro329Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 1,608,510 control chromosomes in the GnomAD database, including 127,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11255 hom., cov: 33)
  • Exomes 𝑓: 0.39 (115778 hom.)
• Consequence: EPHA2 NM_004431.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.511
• Publications: 27 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 1-16138178-G-A is Benign according to our data. Variant chr1-16138178-G-A is described in ClinVar as Benign. ClinVar VariationId is 259398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.511 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA2	NM_004431.5	c.987C>T	p.Pro329Pro	synonymous_variant	Exon 5 of 17	ENST00000358432.8	NP_004422.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8	c.987C>T	p.Pro329Pro	synonymous_variant	Exon 5 of 17	1	NM_004431.5	ENSP00000351209.5
EPHA2	ENST00000480202.1	n.192C>T		non_coding_transcript_exon_variant	Exon 3 of 6	5

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57538 AN: 151990 Hom.: 11246 Cov.: 33

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.405

GnomAD2 exomes AF: 0.377 AC: 91745 AN: 243348 AF XY: 0.386

Gnomad AFR exome AF: 0.351

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.448

Gnomad EAS exome AF: 0.126

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.401

GnomAD4 exome AF: 0.394 AC: 573757 AN: 1456402 Hom.: 115778 Cov.: 80 AF XY: 0.397 AC XY: 287863 AN XY: 724632

African (AFR) AF: 0.356 AC: 11924 AN: 33470

American (AMR) AF: 0.362 AC: 16144 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 11792 AN: 26120

East Asian (EAS) AF: 0.109 AC: 4319 AN: 39654

South Asian (SAS) AF: 0.459 AC: 39589 AN: 86210

European-Finnish (FIN) AF: 0.342 AC: 16685 AN: 48754

Middle Eastern (MID) AF: 0.476 AC: 2742 AN: 5766

European-Non Finnish (NFE) AF: 0.402 AC: 446768 AN: 1111560

Other (OTH) AF: 0.394 AC: 23794 AN: 60318

GnomAD4 genome AF: 0.378 AC: 57569 AN: 152108 Hom.: 11255 Cov.: 33 AF XY: 0.377 AC XY: 28068 AN XY: 74356

African (AFR) AF: 0.352 AC: 14583 AN: 41472

American (AMR) AF: 0.400 AC: 6119 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1547 AN: 3472

East Asian (EAS) AF: 0.124 AC: 640 AN: 5174

South Asian (SAS) AF: 0.450 AC: 2175 AN: 4828

European-Finnish (FIN) AF: 0.339 AC: 3588 AN: 10578

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27479 AN: 67974

Other (OTH) AF: 0.408 AC: 862 AN: 2114

Alfa AF: 0.400 Hom.: 16147

Bravo AF: 0.375

Asia WGS AF: 0.325 AC: 1130 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 6 multiple types Benign:3

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

May 01, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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	-0.61
CADD	Benign	6.1
DANN	Benign	0.72
PhyloP100		-0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2230597; hg19: chr1-16464673; COSMIC: COSV64452406; COSMIC: COSV64452406;