NM_001136018.4:c.852C>T

Variant names:

• chr1-225839958-C-T
• rs2292568
• NM_001136018.4:c.852C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001136018.4(EPHX1):​c.852C>T​(p.Pro284Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0467 in 1,614,140 control chromosomes in the GnomAD database, including 2,264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (227 hom., cov: 32)
  • Exomes 𝑓: 0.047 (2037 hom.)
• Consequence: EPHX1 NM_001136018.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0660
• Publications: 18 publications found

Genes affected

EPHX1 (HGNC:3401): (epoxide hydrolase 1) Epoxide hydrolase is a critical biotransformation enzyme that converts epoxides from the degradation of aromatic compounds to trans-dihydrodiols which can be conjugated and excreted from the body. Epoxide hydrolase functions in both the activation and detoxification of epoxides. Mutations in this gene cause preeclampsia, epoxide hydrolase deficiency or increased epoxide hydrolase activity. Alternatively spliced transcript variants encoding the same protein have been found for this gene.[provided by RefSeq, Dec 2008]

EPHX1 Gene-Disease associations (from GenCC):

• familial hypercholanemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-225839958-C-T is Benign according to our data. Variant chr1-225839958-C-T is described in ClinVar as Benign. ClinVar VariationId is 1295081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136018.4. 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
	EPHX1	NM_001136018.4	MANE Select	c.852C>T	p.Pro284Pro	synonymous	Exon 6 of 9	NP_001129490.1	R4SBI6
	EPHX1	NM_000120.4		c.852C>T	p.Pro284Pro	synonymous	Exon 6 of 9	NP_000111.1	R4SBI6
	EPHX1	NM_001291163.2		c.852C>T	p.Pro284Pro	synonymous	Exon 6 of 9	NP_001278092.1	P07099

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHX1	ENST00000272167.10	TSL:1 MANE Select	c.852C>T	p.Pro284Pro	synonymous	Exon 6 of 9	ENSP00000272167.5	P07099
	EPHX1	ENST00000366837.5	TSL:1	c.852C>T	p.Pro284Pro	synonymous	Exon 6 of 9	ENSP00000355802.4	P07099
	EPHX1	ENST00000614058.4	TSL:1	c.852C>T	p.Pro284Pro	synonymous	Exon 6 of 9	ENSP00000480004.1	P07099

Frequencies

GnomAD3 genomes AF: 0.0459 AC: 6983 AN: 152154 Hom.: 222 Cov.: 32

Gnomad AFR AF: 0.0272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0493

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0907

Gnomad FIN AF: 0.0814

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0399

Gnomad OTH AF: 0.0503

GnomAD2 exomes AF: 0.0605 AC: 15221 AN: 251488 AF XY: 0.0615

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.0567

Gnomad ASJ exome AF: 0.0621

Gnomad EAS exome AF: 0.151

Gnomad FIN exome AF: 0.0814

Gnomad NFE exome AF: 0.0409

Gnomad OTH exome AF: 0.0507

GnomAD4 exome AF: 0.0468 AC: 68383 AN: 1461868 Hom.: 2037 Cov.: 32 AF XY: 0.0483 AC XY: 35092 AN XY: 727236

African (AFR) AF: 0.0238 AC: 797 AN: 33478

American (AMR) AF: 0.0594 AC: 2657 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0595 AC: 1556 AN: 26134

East Asian (EAS) AF: 0.147 AC: 5841 AN: 39700

South Asian (SAS) AF: 0.0906 AC: 7819 AN: 86258

European-Finnish (FIN) AF: 0.0779 AC: 4163 AN: 53420

Middle Eastern (MID) AF: 0.0540 AC: 311 AN: 5764

European-Non Finnish (NFE) AF: 0.0380 AC: 42214 AN: 1111996

Other (OTH) AF: 0.0501 AC: 3025 AN: 60394

GnomAD4 genome AF: 0.0460 AC: 7003 AN: 152272 Hom.: 227 Cov.: 32 AF XY: 0.0484 AC XY: 3606 AN XY: 74452

African (AFR) AF: 0.0273 AC: 1135 AN: 41548

American (AMR) AF: 0.0495 AC: 757 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 219 AN: 3470

East Asian (EAS) AF: 0.145 AC: 750 AN: 5174

South Asian (SAS) AF: 0.0910 AC: 439 AN: 4826

European-Finnish (FIN) AF: 0.0814 AC: 864 AN: 10608

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0399 AC: 2716 AN: 68026

Other (OTH) AF: 0.0560 AC: 118 AN: 2108

Alfa AF: 0.0427 Hom.: 605

Bravo AF: 0.0423

Asia WGS AF: 0.137 AC: 474 AN: 3478

EpiCase AF: 0.0413

EpiControl AF: 0.0403

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.6
DANN	Benign	0.75
PhyloP100		0.066
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2292568; hg19: chr1-226027659; COSMIC: COSV55299530; COSMIC: COSV55299530;