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: 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

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.

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.987C>T	p.Pro329Pro	synonymous	Exon 5 of 17	NP_004422.2
	EPHA2	NM_001329090.2		c.825C>T	p.Pro275Pro	synonymous	Exon 4 of 16	NP_001316019.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA2	ENST00000358432.8	TSL:1 MANE Select	c.987C>T	p.Pro329Pro	synonymous	Exon 5 of 17	ENSP00000351209.5	P29317-1
	EPHA2	ENST00000917106.1		c.987C>T	p.Pro329Pro	synonymous	Exon 5 of 17	ENSP00000587165.1
	EPHA2	ENST00000863593.1		c.987C>T	p.Pro329Pro	synonymous	Exon 5 of 17	ENSP00000533652.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Cataract 6 multiple types (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;