rs762551

chr15-74749576-C-Achr15-74749576-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000761.5(CYP1A2):c.-9-154C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.672 in 152,062 control chromosomes in the GnomAD database, including 34,665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.67 (34665 hom., cov: 32)
• Consequence: CYP1A2 NM_000761.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.24

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP1A2	NM_000761.5	c.-9-154C>A		intron_variant		ENST00000343932.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1A2	ENST00000343932.5	c.-9-154C>A		intron_variant		1	NM_000761.5	P1

Frequencies

GnomAD3 genomes AF: 0.672 AC: 102144 AN: 151944 Hom.: 34631 Cov.: 32

Gnomad AFR AF: 0.605

Gnomad AMI AF: 0.650

Gnomad AMR AF: 0.706

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.567

Gnomad FIN AF: 0.689

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.712

Gnomad OTH AF: 0.666

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

GnomAD4 genome AF: 0.672 AC: 102235 AN: 152062 Hom.: 34665 Cov.: 32 AF XY: 0.668 AC XY: 49693 AN XY: 74348

Gnomad4 AFR AF: 0.605

Gnomad4 AMR AF: 0.706

Gnomad4 ASJ AF: 0.686

Gnomad4 EAS AF: 0.651

Gnomad4 SAS AF: 0.568

Gnomad4 FIN AF: 0.689

Gnomad4 NFE AF: 0.712

Gnomad4 OTH AF: 0.667

Alfa AF: 0.681 Hom.: 16123

Bravo AF: 0.676

Asia WGS AF: 0.661 AC: 2300 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.0070
DANN	Benign	0.69

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: rs762551; hg19: chr15-75041917; COSMIC: COSV59659144;