rs8181425

Variant names:

• chr10-133556966-T-C
• rs8181425
• ENST00000368520.1:n.3664T>C

Variant summary

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

The ENST00000368520.1(CYP2E1):​n.3664T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,478,170 control chromosomes in the GnomAD database, including 10,624 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1332 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9292 hom.)
• Consequence: CYP2E1 ENST00000368520.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0990
• Publications: 6 publications found

Genes affected

CYP2E1 (HGNC:2631): (cytochrome P450 family 2 subfamily E member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and is induced by ethanol, the diabetic state, and starvation. The enzyme metabolizes both endogenous substrates, such as ethanol, acetone, and acetal, as well as exogenous substrates including benzene, carbon tetrachloride, ethylene glycol, and nitrosamines which are premutagens found in cigarette smoke. Due to its many substrates, this enzyme may be involved in such varied processes as gluconeogenesis, hepatic cirrhosis, diabetes, and cancer. [provided by RefSeq, Jul 2008]

SYCE1 (HGNC:28852): (synaptonemal complex central element protein 1) This gene encodes a member of the synaptonemal complex, which links homologous chromosomes during prophase I of meiosis. The tripartite structure of the complex is highly conserved amongst metazoans. It consists of two lateral elements and a central region formed by transverse elements and a central element. The protein encoded by this gene localizes to the central element and is required for initiation and elongation of the synapsis. Allelic variants of this gene have been associated with premature ovarian failure and spermatogenic failure. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

SYCE1 Gene-Disease associations (from GenCC):

• premature ovarian failure 12

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• spermatogenic failure 15

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYCE1	NM_001143764.3	c.464+101A>G		intron_variant	Intron 7 of 12	ENST00000343131.7	NP_001137236.1
SYCE1	NM_001143763.2	c.464+101A>G		intron_variant	Intron 7 of 12		NP_001137235.1
SYCE1	NM_130784.4	c.356+101A>G		intron_variant	Intron 7 of 12		NP_570140.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYCE1	ENST00000343131.7	c.464+101A>G		intron_variant	Intron 7 of 12	1	NM_001143764.3	ENSP00000341282.5

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20318 AN: 151882 Hom.: 1329 Cov.: 33

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0946

Gnomad OTH AF: 0.126

GnomAD4 exome AF: 0.111 AC: 147293 AN: 1326168 Hom.: 9292 Cov.: 20 AF XY: 0.112 AC XY: 74764 AN XY: 666268

African (AFR) AF: 0.188 AC: 5763 AN: 30724

American (AMR) AF: 0.161 AC: 7140 AN: 44418

Ashkenazi Jewish (ASJ) AF: 0.0982 AC: 2457 AN: 25020

East Asian (EAS) AF: 0.268 AC: 10414 AN: 38928

South Asian (SAS) AF: 0.185 AC: 15327 AN: 82682

European-Finnish (FIN) AF: 0.121 AC: 6431 AN: 53072

Middle Eastern (MID) AF: 0.0858 AC: 474 AN: 5522

European-Non Finnish (NFE) AF: 0.0936 AC: 92631 AN: 989846

Other (OTH) AF: 0.119 AC: 6656 AN: 55956

GnomAD4 genome AF: 0.134 AC: 20331 AN: 152002 Hom.: 1332 Cov.: 33 AF XY: 0.138 AC XY: 10226 AN XY: 74294

African (AFR) AF: 0.183 AC: 7563 AN: 41362

American (AMR) AF: 0.137 AC: 2093 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 350 AN: 3466

East Asian (EAS) AF: 0.253 AC: 1308 AN: 5160

South Asian (SAS) AF: 0.195 AC: 938 AN: 4818

European-Finnish (FIN) AF: 0.121 AC: 1287 AN: 10602

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0946 AC: 6432 AN: 68012

Other (OTH) AF: 0.124 AC: 262 AN: 2106

Alfa AF: 0.116 Hom.: 148

Asia WGS AF: 0.191 AC: 669 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.8
DANN	Benign	0.62
PhyloP100		0.099
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs8181425; hg19: chr10-135370470; COSMIC: COSV58216328;