rs587778875
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000104.4(CYP1B1):βc.868delβ(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 (β β ).
Frequency
Genomes: not found (cov: 33)
Exomes π: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CYP1B1
NM_000104.4 frameshift
NM_000104.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.35
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 135 pathogenic variants in the truncated region.
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 id is 2681137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-38074520-CG-C is described in Lovd as [Pathogenic]. Variant chr2-38074520-CG-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP1B1 | NM_000104.4 | c.868del | p.Arg290AlafsTer3 | frameshift_variant | 2/3 | ENST00000610745.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP1B1 | ENST00000610745.5 | c.868del | p.Arg290AlafsTer3 | frameshift_variant | 2/3 | 1 | NM_000104.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1456096Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 723912
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
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1456096
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31
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0
AN XY:
723912
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
Bravo
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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
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 07, 2022 | - - |
Congenital glaucoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 08, 2023 | 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
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at