chr1-16130268-C-T

Position:

chr1-16130268-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004431.5(EPHA2):c.2627G>A(p.Arg876His) variant causes a missense change. The variant allele was found at a frequency of 0.0236 in 1,613,878 control chromosomes in the GnomAD database, including 560 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 33 hom., cov: 32)

Exomes 𝑓: 0.024 ( 527 hom. )

Consequence

EPHA2
NM_004431.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.78

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007658243).

BP6

Variant 1-16130268-C-T is Benign according to our data. Variant chr1-16130268-C-T is described in ClinVar as [Benign]. Clinvar id is 259391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16130268-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0172 (2616/152272) while in subpopulation NFE AF= 0.0274 (1865/68012). AF 95% confidence interval is 0.0264. There are 33 homozygotes in gnomad4. There are 1242 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2616 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHA2	NM_004431.5 linkuse as main transcript	c.2627G>A	p.Arg876His	missense_variant	15/17	ENST00000358432.8	NP_004422.2	P29317-1A0A024QZA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8 linkuse as main transcript	c.2627G>A	p.Arg876His	missense_variant	15/17	1	NM_004431.5	ENSP00000351209.5		P29317-1

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2616

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00497

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0199

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00651

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0274

Gnomad OTH

AF:

0.0181

GnomAD3 exomes

AF:

0.0171

AC:

4304

AN:

251144

Hom.:

AF XY:

0.0169

AC XY:

2296

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.00523

Gnomad AMR exome

AF:

0.0150

Gnomad ASJ exome

AF:

0.0191

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.00540

Gnomad FIN exome

AF:

0.00772

Gnomad NFE exome

AF:

0.0266

Gnomad OTH exome

AF:

0.0237

GnomAD4 exome

AF:

0.0243

AC:

35459

AN:

1461606

Hom.:

527

Cov.:

AF XY:

0.0235

AC XY:

17090

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.00448

Gnomad4 AMR exome

AF:

0.0159

Gnomad4 ASJ exome

AF:

0.0227

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00559

Gnomad4 FIN exome

AF:

0.00972

Gnomad4 NFE exome

AF:

0.0284

Gnomad4 OTH exome

AF:

0.0218

GnomAD4 genome

AF:

0.0172

AC:

2616

AN:

152272

Hom.:

Cov.:

AF XY:

0.0167

AC XY:

1242

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00496

Gnomad4 AMR

AF:

0.0199

Gnomad4 ASJ

AF:

0.0228

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.00651

Gnomad4 NFE

AF:

0.0274

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0256

Hom.:

Bravo

AF:

0.0183

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0267

AC:

103

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.0256

AC:

220

ExAC

AF:

0.0169

AC:

2054

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0290

EpiControl

AF:

0.0279

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cataract 6 multiple types

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2020	This variant is associated with the following publications: (PMID: 26463840, 29267365, 31484920) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0077

MetaSVM

Benign

-0.36

MutationAssessor

Pathogenic

3.0

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.27

Sift

Uncertain

0.026

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.14

MPC

1.6

ClinPred

0.052

GERP RS

5.6

Varity_R

0.60

gMVP

0.68

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over