rs4646425

Variant names:

• chr15-74750940-C-T
• rs4646425
• NM_000761.5:c.832-249C>T

Variant summary

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

The NM_000761.5(CYP1A2):​c.832-249C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 152,274 control chromosomes in the GnomAD database, including 71 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 0.023 (71 hom., cov: 32)
• Consequence: CYP1A2 NM_000761.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.416
• Publications: 25 publications found

Genes affected

CYP1A2 (HGNC:2596): (cytochrome P450 family 1 subfamily A member 2) 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. The protein encoded by this gene localizes to the endoplasmic reticulum and its expression is induced by some polycyclic aromatic hydrocarbons (PAHs), some of which are found in cigarette smoke. The enzyme's endogenous substrate is unknown; however, it is able to metabolize some PAHs to carcinogenic intermediates. Other xenobiotic substrates for this enzyme include caffeine, aflatoxin B1, and acetaminophen. The transcript from this gene contains four Alu sequences flanked by direct repeats in the 3' untranslated region. [provided by RefSeq, Jul 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP1A2	NM_000761.5	c.832-249C>T		intron_variant	Intron 2 of 6	ENST00000343932.5	NP_000752.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP1A2	ENST00000343932.5	c.832-249C>T		intron_variant	Intron 2 of 6	1	NM_000761.5	ENSP00000342007.4

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3549 AN: 152156 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0274

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.0740

Gnomad SAS AF: 0.0849

Gnomad FIN AF: 0.0374

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0278

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0233 AC: 3546 AN: 152274 Hom.: 71 Cov.: 32 AF XY: 0.0261 AC XY: 1943 AN XY: 74440

African (AFR) AF: 0.00431 AC: 179 AN: 41560

American (AMR) AF: 0.0273 AC: 418 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 200 AN: 3472

East Asian (EAS) AF: 0.0734 AC: 380 AN: 5176

South Asian (SAS) AF: 0.0856 AC: 413 AN: 4824

European-Finnish (FIN) AF: 0.0374 AC: 397 AN: 10610

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0215 AC: 1463 AN: 68018

Other (OTH) AF: 0.0275 AC: 58 AN: 2110

Alfa AF: 0.0221 Hom.: 167

Bravo AF: 0.0201

Asia WGS AF: 0.0660 AC: 229 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.8
DANN	Benign	0.50
PhyloP100		-0.42
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: rs4646425; hg19: chr15-75043281;