Genetic Variant EPHX2:p.Cys309Phe (chr8-27518053-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001979.6(EPHX2):c.926G>T(p.Cys309Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

EPHX2
NM_001979.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.78

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27625895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHX2	NM_001979.6 link	c.926G>T	p.Cys309Phe	missense_variant	Exon 9 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.926G>T	p.Cys309Phe	missense_variant	Exon 9 of 19	1	NM_001979.6	ENSP00000430269.1		P34913-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000420

AC:

AN:

238064

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000331

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445556

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719008

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32628

American (AMR)

AF:

0.0000246

AC:

AN:

40700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25800

East Asian (EAS)

AF:

0.00

AC:

AN:

39424

South Asian (SAS)

AF:

0.00

AC:

AN:

82538

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105602

Other (OTH)

AF:

0.00

AC:

AN:

59864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 23, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.926G>T (p.C309F) alteration is located in exon 9 (coding exon 9) of the EPHX2 gene. This alteration results from a G to T substitution at nucleotide position 926, causing the cysteine (C) at amino acid position 309 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.11

T;.;.;.;.

Eigen

Benign

0.051

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.88

D;D;D;D;D

M_CAP

Benign

0.0075

MetaRNN

Benign

0.28

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;.;.;.;.

PhyloP100

2.8

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.8

N;N;N;N;N

REVEL

Benign

0.11

Sift

Uncertain

0.010

D;D;D;D;D

Sift4G

Uncertain

0.012

D;D;D;D;D

Polyphen

0.80

P;.;.;.;B

Vest4

0.27

MutPred

0.62

Gain of phosphorylation at Y308 (P = 0.1624);.;.;.;.;

MVP

0.45

MPC

0.37

ClinPred

0.72

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.76

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over