Genetic Variant EPHX2:p.Lys55Arg (chr8-27500988-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001979.6(EPHX2):c.164A>G(p.Lys55Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,612,256 control chromosomes in the GnomAD database, including 10,110 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.13 ( 1480 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8630 hom. )

Consequence

EPHX2
NM_001979.6 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.28

Publications

96 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013301373).

BP6

Variant 8-27500988-A-G is Benign according to our data. Variant chr8-27500988-A-G is described in ClinVar as Benign. ClinVar VariationId is 3059509.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHX2	NM_001979.6 link	c.164A>G	p.Lys55Arg	missense_variant	Exon 2 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.164A>G	p.Lys55Arg	missense_variant	Exon 2 of 19	1	NM_001979.6	ENSP00000430269.1		P34913-1

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19571

AN:

152064

Hom.:

1465

Cov.:

show subpopulations

Gnomad AFR

AF:

0.219

Gnomad AMI

AF:

0.0493

Gnomad AMR

AF:

0.0925

Gnomad ASJ

AF:

0.0839

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.0646

Gnomad FIN

AF:

0.0855

Gnomad MID

AF:

0.0796

Gnomad NFE

AF:

0.106

Gnomad OTH

AF:

0.130

GnomAD2 exomes

AF:

0.0868

AC:

21707

AN:

249942

AF XY:

0.0862

show subpopulations

Gnomad AFR exome

AF:

0.217

Gnomad AMR exome

AF:

0.0504

Gnomad ASJ exome

AF:

0.0819

Gnomad EAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.0823

Gnomad NFE exome

AF:

0.101

Gnomad OTH exome

AF:

0.0942

GnomAD4 exome

AF:

0.102

AC:

149556

AN:

1460074

Hom.:

8630

Cov.:

AF XY:

0.101

AC XY:

73459

AN XY:

726392

show subpopulations

African (AFR)

AF:

0.226

AC:

7538

AN:

33296

American (AMR)

AF:

0.0550

AC:

2454

AN:

44578

Ashkenazi Jewish (ASJ)

AF:

0.0809

AC:

2112

AN:

26098

East Asian (EAS)

AF:

0.000202

AC:

AN:

39672

South Asian (SAS)

AF:

0.0651

AC:

5601

AN:

86022

European-Finnish (FIN)

AF:

0.0806

AC:

4302

AN:

53348

Middle Eastern (MID)

AF:

0.107

AC:

617

AN:

5762

European-Non Finnish (NFE)

AF:

0.109

AC:

120691

AN:

1110972

Other (OTH)

AF:

0.103

AC:

6233

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

6212

12425

18637

24850

31062

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4482

8964

13446

17928

22410

<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:

0.129

AC:

19621

AN:

152182

Hom.:

1480

Cov.:

AF XY:

0.126

AC XY:

9366

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.220

AC:

9119

AN:

41492

American (AMR)

AF:

0.0924

AC:

1413

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0839

AC:

291

AN:

3468

East Asian (EAS)

AF:

0.00135

AC:

AN:

5186

South Asian (SAS)

AF:

0.0639

AC:

308

AN:

4822

European-Finnish (FIN)

AF:

0.0855

AC:

906

AN:

10600

Middle Eastern (MID)

AF:

0.0788

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.106

AC:

7239

AN:

68000

Other (OTH)

AF:

0.128

AC:

270

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

852

1704

2555

3407

4259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

204

408

612

816

1020

<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:

0.111

Hom.:

3023

Bravo

AF:

0.134

TwinsUK

AF:

0.122

AC:

453

ALSPAC

AF:

0.107

AC:

413

ESP6500AA

AF:

0.218

AC:

959

ESP6500EA

AF:

0.104

AC:

895

ExAC

AF:

0.0899

AC:

10920

Asia WGS

AF:

0.0380

AC:

133

AN:

3478

EpiCase

AF:

0.103

EpiControl

AF:

0.110

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

EPHX2-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.035

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.065

T;T;.;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0034

LIST_S2

Benign

0.28

T;T;T;T;T

MetaRNN

Benign

0.0013

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.82

N;.;.;.;.

PhyloP100

-1.3

PrimateAI

Benign

0.31

PROVEAN

Benign

0.49

N;N;N;N;N

REVEL

Benign

0.028

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0

B;.;.;.;B

Vest4

0.096

MPC

0.070

ClinPred

0.00030

GERP RS

-5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.057

gMVP

0.38

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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