8-27491270-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001979.6(EPHX2):c.62G>A(p.Gly21Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G21A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: EPHX2 NM_001979.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.575

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.096276134).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHX2	NM_001979.6	c.62G>A	p.Gly21Asp	missense_variant	1/19	ENST00000521400.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHX2	ENST00000521400.6	c.62G>A	p.Gly21Asp	missense_variant	1/19	1	NM_001979.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1427156 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 709476

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.62G>A (p.G21D) alteration is located in exon 1 (coding exon 1) of the EPHX2 gene. This alteration results from a G to A substitution at nucleotide position 62, causing the glycine (G) at amino acid position 21 to be replaced by an aspartic acid (D). 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	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	12
Dann	Benign	0.92
DEOGEN2	Benign	0.12	T;T;.;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.096	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.069
Sift	Benign	0.25	T;T;D;T
Sift4G	Benign	0.57	T;T;T;T
Polyphen		0.28	B;.;.;B
Vest4		0.16
MutPred		0.38		Loss of catalytic residue at V22 (P = 0.0528);Loss of catalytic residue at V22 (P = 0.0528);Loss of catalytic residue at V22 (P = 0.0528);Loss of catalytic residue at V22 (P = 0.0528);
MVP		0.29
MPC		0.51
ClinPred		0.13	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.17
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs72473930; hg19: chr8-27348787;