dbSNP rs751141: EPHX2:p.Arg287Gln (chr8-27516348-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001979.6(EPHX2):c.860G>A(p.Arg287Gln) variant causes a missense change. The variant allele was found at a frequency of 0.108 in 1,613,354 control chromosomes in the GnomAD database, including 10,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R287W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.10 ( 917 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9234 hom. )

Consequence

EPHX2
NM_001979.6 missense

Scores

Clinical Significance

risk factor no assertion criteria provided O:1

Conservation

PhyloP100: 7.19

Publications

169 publications found

Variant links:

Genes affected

EPHX2 (HGNC:3402): (epoxide hydrolase 2) This gene encodes a member of the epoxide hydrolase family. The protein, found in both the cytosol and peroxisomes, binds to specific epoxides and converts them to the corresponding dihydrodiols. Mutations in this gene have been associated with familial hypercholesterolemia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2012]

EPHX2 Gene-Disease associations (from GenCC):

hypercholesterolemia, familial, 1
Inheritance: AD Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

EPHX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024335682).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHX2	NM_001979.6 link	c.860G>A	p.Arg287Gln	missense_variant	Exon 8 of 19	ENST00000521400.6	NP_001970.2	P34913-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHX2	ENST00000521400.6 link	c.860G>A	p.Arg287Gln	missense_variant	Exon 8 of 19	1	NM_001979.6	ENSP00000430269.1		P34913-1

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

15880

AN:

151900

Hom.:

918

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0939

Gnomad AMI

AF:

0.129

Gnomad AMR

AF:

0.115

Gnomad ASJ

AF:

0.0646

Gnomad EAS

AF:

0.222

Gnomad SAS

AF:

0.129

Gnomad FIN

AF:

0.0890

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.103

Gnomad OTH

AF:

0.101

GnomAD2 exomes

AF:

0.117

AC:

29461

AN:

251406

AF XY:

0.113

show subpopulations

Gnomad AFR exome

AF:

0.0890

Gnomad AMR exome

AF:

0.173

Gnomad ASJ exome

AF:

0.0662

Gnomad EAS exome

AF:

0.215

Gnomad FIN exome

AF:

0.0987

Gnomad NFE exome

AF:

0.0978

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.109

AC:

158952

AN:

1461336

Hom.:

9234

Cov.:

AF XY:

0.108

AC XY:

78254

AN XY:

726946

show subpopulations

African (AFR)

AF:

0.0955

AC:

3198

AN:

33470

American (AMR)

AF:

0.163

AC:

7286

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0680

AC:

1777

AN:

26136

East Asian (EAS)

AF:

0.207

AC:

8220

AN:

39688

South Asian (SAS)

AF:

0.114

AC:

9784

AN:

86200

European-Finnish (FIN)

AF:

0.103

AC:

5515

AN:

53408

Middle Eastern (MID)

AF:

0.0645

AC:

372

AN:

5764

European-Non Finnish (NFE)

AF:

0.105

AC:

116308

AN:

1111586

Other (OTH)

AF:

0.108

AC:

6492

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

7469

14939

22408

29878

37347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4426

8852

13278

17704

22130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.105

AC:

15889

AN:

152018

Hom.:

917

Cov.:

AF XY:

0.105

AC XY:

7774

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.0939

AC:

3892

AN:

41458

American (AMR)

AF:

0.115

AC:

1753

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0646

AC:

224

AN:

3470

East Asian (EAS)

AF:

0.222

AC:

1139

AN:

5140

South Asian (SAS)

AF:

0.129

AC:

620

AN:

4800

European-Finnish (FIN)

AF:

0.0890

AC:

943

AN:

10594

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.103

AC:

6971

AN:

67960

Other (OTH)

AF:

0.0999

AC:

211

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

704

1408

2111

2815

3519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

360

540

720

900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.102

Hom.:

2899

Bravo

AF:

0.106

TwinsUK

AF:

0.0987

AC:

366

ALSPAC

AF:

0.106

AC:

408

ESP6500AA

AF:

0.0937

AC:

413

ESP6500EA

AF:

0.107

AC:

916

ExAC

AF:

0.115

AC:

14003

Asia WGS

AF:

0.152

AC:

529

AN:

3478

EpiCase

AF:

0.0935

EpiControl

AF:

0.0886

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Other:1

May 27, 2005

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.33

T;.;.;.;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

D;D;D;D;D

MetaRNN

Benign

0.0024

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;.;.;.;.

PhyloP100

7.2

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.3

D;D;D;D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0080

D;D;D;D;D

Sift4G

Uncertain

0.026

D;D;D;D;D

Polyphen

1.0

D;.;.;.;D

Vest4

0.61

MPC

0.37

ClinPred

0.0096

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.79

Mutation Taster

=52/48

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over