rs41507953

chr8-27500988-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1480 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8630 hom.)
• Consequence: EPHX2 NM_001979.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.28

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 3059509.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
EPHX2	NM_001979.6	c.164A>G	p.Lys55Arg	missense_variant	2/19	ENST00000521400.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHX2	ENST00000521400.6	c.164A>G	p.Lys55Arg	missense_variant	2/19	1	NM_001979.6	P1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19571 AN: 152064 Hom.: 1465 Cov.: 32

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

GnomAD3 exomes AF: 0.0868 AC: 21707 AN: 249942 Hom.: 1237 AF XY: 0.0862 AC XY: 11654 AN XY: 135146

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 SAS exome AF: 0.0613

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.: 31 AF XY: 0.101 AC XY: 73459 AN XY: 726392

Gnomad4 AFR exome AF: 0.226

Gnomad4 AMR exome AF: 0.0550

Gnomad4 ASJ exome AF: 0.0809

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0651

Gnomad4 FIN exome AF: 0.0806

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.103

GnomAD4 genome AF: 0.129 AC: 19621 AN: 152182 Hom.: 1480 Cov.: 32 AF XY: 0.126 AC XY: 9366 AN XY: 74434

Gnomad4 AFR AF: 0.220

Gnomad4 AMR AF: 0.0924

Gnomad4 ASJ AF: 0.0839

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0639

Gnomad4 FIN AF: 0.0855

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.128

Alfa AF: 0.105 Hom.: 1771

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: criteria provided, single submitter

Submissions by phenotype

EPHX2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.035
Dann	Benign	0.29
DEOGEN2	Benign	0.065	T;T;.;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.28	T;T;T;T;T
MetaRNN	Benign	0.0013	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.82	N;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.31	T
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	T
GERP RS		-5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs41507953; hg19: chr8-27358505; COSMIC: COSV66844518; COSMIC: COSV66844518;