rs12405694

Variant names:

• chr1-16144960-A-G
• rs12405694
• NM_004431.5:c.823+3418T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004431.5(EPHA2):​c.823+3418T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 152,142 control chromosomes in the GnomAD database, including 7,304 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (7304 hom., cov: 33)
• Consequence: EPHA2 NM_004431.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA2	NM_004431.5	c.823+3418T>C		intron_variant	Intron 3 of 16	ENST00000358432.8	NP_004422.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8	c.823+3418T>C		intron_variant	Intron 3 of 16	1	NM_004431.5	ENSP00000351209.5
EPHA2	ENST00000480202.1	n.28+1463T>C		intron_variant	Intron 1 of 5	5

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45503 AN: 152022 Hom.: 7297 Cov.: 33

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.338

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.299 AC: 45524 AN: 152142 Hom.: 7304 Cov.: 33 AF XY: 0.298 AC XY: 22164 AN XY: 74402

African (AFR) AF: 0.235 AC: 9751 AN: 41488

American (AMR) AF: 0.357 AC: 5461 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1335 AN: 3472

East Asian (EAS) AF: 0.0259 AC: 134 AN: 5176

South Asian (SAS) AF: 0.329 AC: 1588 AN: 4830

European-Finnish (FIN) AF: 0.276 AC: 2922 AN: 10604

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23170 AN: 67966

Other (OTH) AF: 0.340 AC: 717 AN: 2110

Alfa AF: 0.315 Hom.: 1328

Bravo AF: 0.298

Asia WGS AF: 0.196 AC: 683 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.062
DANN	Benign	0.70
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12405694; hg19: chr1-16471455;