rs751141

Variant names:

• chr8-27516348-G-A
• rs751141
• NM_001979.6:c.860G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-27516348-G-A
• chr8-27516348-G-C
• chr8-27516348-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 7.19
• Publications: 169 publications found

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)

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001979.6. 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
	EPHX2	NM_001979.6	MANE Select	c.860G>A	p.Arg287Gln	missense	Exon 8 of 19	NP_001970.2
	EPHX2	NM_001414016.1		c.860G>A	p.Arg287Gln	missense	Exon 8 of 17	NP_001400945.1
	EPHX2	NM_001414017.1		c.860G>A	p.Arg287Gln	missense	Exon 8 of 19	NP_001400946.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHX2	ENST00000521400.6	TSL:1 MANE Select	c.860G>A	p.Arg287Gln	missense	Exon 8 of 19	ENSP00000430269.1	P34913-1
	EPHX2	ENST00000520623.5	TSL:1	n.944G>A		non_coding_transcript_exon	Exon 8 of 14
	EPHX2	ENST00000872957.1		c.860G>A	p.Arg287Gln	missense	Exon 9 of 20	ENSP00000543016.1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15880 AN: 151900 Hom.: 918 Cov.: 32

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

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.: 31 AF XY: 0.108 AC XY: 78254 AN XY: 726946

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

GnomAD4 genome AF: 0.105 AC: 15889 AN: 152018 Hom.: 917 Cov.: 32 AF XY: 0.105 AC XY: 7774 AN XY: 74300

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: 19 AN: 294

European-Non Finnish (NFE) AF: 0.103 AC: 6971 AN: 67960

Other (OTH) AF: 0.0999 AC: 211 AN: 2112

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

ClinVar submissions

Significance: risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Hypercholesterolemia, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.2
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.61
MPC		0.37
ClinPred		0.0096	T
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)

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

Other links and lift over

dbSNP: rs751141; hg19: chr8-27373865; COSMIC: COSV66844144; COSMIC: COSV66844144;