rs2855658

Positions:

• chr2-38069747-T-C

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.*975A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.531 in 197,520 control chromosomes in the GnomAD database, including 31,322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (22357 hom., cov: 31)
  • Exomes 𝑓: 0.61 (8965 hom.)
• Consequence: CYP1B1 NM_000104.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.452

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-38069747-T-C is Benign according to our data. Variant chr2-38069747-T-C is described in ClinVar as [Benign]. Clinvar id is 335936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP1B1	NM_000104.4	c.*975A>G		3_prime_UTR_variant	3/3	ENST00000610745.5	NP_000095.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP1B1	ENST00000610745	c.*975A>G		3_prime_UTR_variant	3/3	1	NM_000104.4	ENSP00000478561.1
CYP1B1	ENST00000490576	c.*975A>G		3_prime_UTR_variant	3/3	4		ENSP00000478839.2
CYP1B1	ENST00000491456.1	n.89-474A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77140 AN: 151864 Hom.: 22361 Cov.: 31

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.678

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.889

Gnomad SAS AF: 0.808

Gnomad FIN AF: 0.642

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.566

Gnomad OTH AF: 0.554

GnomAD4 exome AF: 0.609 AC: 27717 AN: 45536 Hom.: 8965 Cov.: 0 AF XY: 0.609 AC XY: 12910 AN XY: 21214

Gnomad4 AFR exome AF: 0.223

Gnomad4 AMR exome AF: 0.685

Gnomad4 ASJ exome AF: 0.507

Gnomad4 EAS exome AF: 0.865

Gnomad4 SAS exome AF: 0.815

Gnomad4 FIN exome AF: 0.714

Gnomad4 NFE exome AF: 0.574

Gnomad4 OTH exome AF: 0.585

GnomAD4 genome AF: 0.508 AC: 77151 AN: 151984 Hom.: 22357 Cov.: 31 AF XY: 0.522 AC XY: 38757 AN XY: 74294

Gnomad4 AFR AF: 0.228

Gnomad4 AMR AF: 0.678

Gnomad4 ASJ AF: 0.497

Gnomad4 EAS AF: 0.889

Gnomad4 SAS AF: 0.808

Gnomad4 FIN AF: 0.642

Gnomad4 NFE AF: 0.566

Gnomad4 OTH AF: 0.557

Alfa AF: 0.559 Hom.: 36771

Bravo AF: 0.497

Asia WGS AF: 0.797 AC: 2766 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glaucoma 3A 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. -

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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.9
DANN	Benign	0.62

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: rs2855658; hg19: chr2-38296890;