rs138818894

Variant names:

• chr1-16125242-C-G
• rs138818894
• NM_004431.5:c.2904G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-16125242-C-G
• chr1-16125242-C-A
• chr1-16125242-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004431.5(EPHA2):​c.2904G>C​(p.Gln968His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,613,984 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (12 hom.)
• Consequence: EPHA2 NM_004431.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.361
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008738786).
• BP6: Variant 1-16125242-C-G is Benign according to our data. Variant chr1-16125242-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 293406.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00172 (262/152290) while in subpopulation NFE AF = 0.00278 (189/68028). AF 95% confidence interval is 0.00245. There are 0 homozygotes in GnomAd4. There are 128 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.2904G>C	p.Gln968His	missense	Exon 17 of 17	NP_004422.2
	EPHA2	NM_001329090.2		c.2742G>C	p.Gln914His	missense	Exon 16 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.2904G>C	p.Gln968His	missense	Exon 17 of 17	ENSP00000351209.5	P29317-1
	EPHA2	ENST00000917106.1		c.2919G>C	p.Gln973His	missense	Exon 17 of 17	ENSP00000587165.1
	EPHA2	ENST00000863593.1		c.2883G>C	p.Gln961His	missense	Exon 17 of 17	ENSP00000533652.1

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 261 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00278

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00187 AC: 467 AN: 250282 AF XY: 0.00184

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000811

Gnomad ASJ exome AF: 0.00418

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000650

Gnomad NFE exome AF: 0.00294

Gnomad OTH exome AF: 0.00328

GnomAD4 exome AF: 0.00248 AC: 3629 AN: 1461694 Hom.: 12 Cov.: 30 AF XY: 0.00244 AC XY: 1776 AN XY: 727124

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000760 AC: 34 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 120 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000986 AC: 85 AN: 86210

European-Finnish (FIN) AF: 0.000506 AC: 27 AN: 53326

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00288 AC: 3206 AN: 1111972

Other (OTH) AF: 0.00240 AC: 145 AN: 60390

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.00172 AC XY: 128 AN XY: 74462

African (AFR) AF: 0.000626 AC: 26 AN: 41562

American (AMR) AF: 0.000981 AC: 15 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00278 AC: 189 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00249 Hom.: 1

Bravo AF: 0.00171

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00203 AC: 247

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00326

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Cataract 6 multiple types (2)
-	-	1	EPHA2-related disorder (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.36
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.18
Sift	Benign	0.082	T
Sift4G	Benign	0.11	T
Polyphen		0.031	B
Vest4		0.54
MutPred		0.73		Gain of ubiquitination at K966 (P = 0.0767)
MVP		0.77
MPC		0.62
ClinPred		0.018	T
GERP RS		-2.2
Varity_R		0.21
gMVP		0.90
Mutation Taster		=90/10	polymorphism

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: rs138818894; hg19: chr1-16451737;