Genetic Variant CYP1B1:p.Arg290AlafsTer3 (chr2-38074520-CG-C) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000104.4(CYP1B1):c.868delC(p.Arg290AlafsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CYP1B1
NM_000104.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 1.35

Publications

7 publications found

Variant links:

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 links:

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

CYP1B1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-38074520-CG-C is Pathogenic according to our data. Variant chr2-38074520-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2681137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP1B1	NM_000104.4 link	c.868delC	p.Arg290AlafsTer3	frameshift_variant	Exon 2 of 3	ENST00000610745.5	NP_000095.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP1B1	ENST00000610745.5 link	c.868delC	p.Arg290AlafsTer3	frameshift_variant	Exon 2 of 3	1	NM_000104.4	ENSP00000478561.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1456096

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723912

African (AFR)

AF:

0.00

AC:

AN:

33434

American (AMR)

AF:

0.00

AC:

AN:

43626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25962

East Asian (EAS)

AF:

0.00

AC:

AN:

39482

South Asian (SAS)

AF:

0.00

AC:

AN:

85454

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109638

Other (OTH)

AF:

0.00

AC:

AN:

60154

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Anterior segment dysgenesis 6

Pathogenic:1

Nov 07, 2022

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital glaucoma

Pathogenic:1

Mar 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with CYP1B1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg290Alafs*3) in the CYP1B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP1B1 are known to be pathogenic (PMID: 9097971, 9497261, 19234632). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over