rs41507953

Variant names:

• chr8-27500988-A-G
• rs41507953
• NM_001979.6:c.164A>G
• EPHX2 p.Lys55Arg

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 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
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.28
• Publications: 97 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 -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.

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.164A>G	p.Lys55Arg	missense	Exon 2 of 19	NP_001970.2
	EPHX2	NM_001414016.1		c.164A>G	p.Lys55Arg	missense	Exon 2 of 17	NP_001400945.1
	EPHX2	NM_001414017.1		c.164A>G	p.Lys55Arg	missense	Exon 2 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.164A>G	p.Lys55Arg	missense	Exon 2 of 19	ENSP00000430269.1	P34913-1
	EPHX2	ENST00000520623.5	TSL:1	n.248A>G		non_coding_transcript_exon	Exon 2 of 14
	EPHX2	ENST00000872957.1		c.164A>G	p.Lys55Arg	missense	Exon 3 of 20	ENSP00000543016.1

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

GnomAD2 exomes AF: 0.0868 AC: 21707 AN: 249942 AF XY: 0.0862

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

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: 8 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

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

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: 7 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: 23 AN: 292

European-Non Finnish (NFE) AF: 0.106 AC: 7239 AN: 68000

Other (OTH) AF: 0.128 AC: 270 AN: 2112

Alfa AF: 0.111 Hom.: 3023

Bravo AF: 0.134

Asia WGS AF: 0.0380 AC: 133 AN: 3478

EpiCase AF: 0.103

EpiControl AF: 0.110

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	EPHX2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.82	N
PhyloP100		-1.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.028
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
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)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41507953;

hg19: chr8-27358505;

COSMIC: COSV66844518;

COSMIC: COSV66844518;