rs2617266

chr2-38075401-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000104.4(CYP1B1):c.-1-12C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,609,792 control chromosomes in the GnomAD database, including 66,035 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6311 hom., cov: 33)
  • Exomes 𝑓: 0.28 (59724 hom.)
• Consequence: CYP1B1 NM_000104.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001679
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0280

Genes affected

CYP1B1 (HGNC:2597): (cytochrome P450 family 1 subfamily B 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. The enzyme encoded by this gene localizes to the endoplasmic reticulum and metabolizes procarcinogens such as polycyclic aromatic hydrocarbons and 17beta-estradiol. Mutations in this gene have been associated with primary congenital glaucoma; therefore it is thought that the enzyme also metabolizes a signaling molecule involved in eye development, possibly a steroid. [provided by RefSeq, Jul 2008]

CYP1B1-AS1 (HGNC:28543): (CYP1B1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 2-38075401-G-A is Benign according to our data. Variant chr2-38075401-G-A is described in ClinVar as [Benign]. Clinvar id is 166974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-38075401-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP1B1	NM_000104.4	c.-1-12C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000610745.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1B1	ENST00000610745.5	c.-1-12C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000104.4	P1

Frequencies

GnomAD3 genomes AF: 0.283 AC: 42994 AN: 152072 Hom.: 6305 Cov.: 33

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.506

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.265

GnomAD3 exomes AF: 0.293 AC: 70960 AN: 242504 Hom.: 10583 AF XY: 0.297 AC XY: 39066 AN XY: 131754

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.295

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.189

Gnomad SAS exome AF: 0.373

Gnomad FIN exome AF: 0.359

Gnomad NFE exome AF: 0.286

Gnomad OTH exome AF: 0.291

GnomAD4 exome AF: 0.283 AC: 412441 AN: 1457602 Hom.: 59724 Cov.: 34 AF XY: 0.286 AC XY: 207294 AN XY: 724966

Gnomad4 AFR exome AF: 0.262

Gnomad4 AMR exome AF: 0.294

Gnomad4 ASJ exome AF: 0.224

Gnomad4 EAS exome AF: 0.148

Gnomad4 SAS exome AF: 0.368

Gnomad4 FIN exome AF: 0.358

Gnomad4 NFE exome AF: 0.279

Gnomad4 OTH exome AF: 0.281

GnomAD4 genome AF: 0.283 AC: 43021 AN: 152190 Hom.: 6311 Cov.: 33 AF XY: 0.288 AC XY: 21429 AN XY: 74388

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.292

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.180

Gnomad4 SAS AF: 0.379

Gnomad4 FIN AF: 0.366

Gnomad4 NFE AF: 0.285

Gnomad4 OTH AF: 0.272

Alfa AF: 0.284 Hom.: 1257

Bravo AF: 0.271

Asia WGS AF: 0.296 AC: 1028 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Glaucoma 3A Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Anterior segment dysgenesis 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Irido-corneo-trabecular dysgenesis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	10
Dann	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.040
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: rs2617266; hg19: chr2-38302544; COSMIC: COSV53191821; COSMIC: COSV53191821;