chr2-38075234-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000104.4(CYP1B1):c.155C>T(p.Pro52Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000286 in 1,589,128 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00028 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00029 ( 1 hom. )
Consequence
CYP1B1
NM_000104.4 missense
NM_000104.4 missense
Scores
8
5
2
Clinical Significance
Conservation
PhyloP100: 5.53
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.849
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP1B1 | NM_000104.4 | c.155C>T | p.Pro52Leu | missense_variant | 2/3 | ENST00000610745.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP1B1 | ENST00000610745.5 | c.155C>T | p.Pro52Leu | missense_variant | 2/3 | 1 | NM_000104.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000282 AC: 43AN: 152232Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000319 AC: 67AN: 210080Hom.: 0 AF XY: 0.000313 AC XY: 36AN XY: 114932
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GnomAD4 exome AF: 0.000286 AC: 411AN: 1436896Hom.: 1 Cov.: 35 AF XY: 0.000287 AC XY: 205AN XY: 713554
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GnomAD4 genome AF: 0.000282 AC: 43AN: 152232Hom.: 0 Cov.: 34 AF XY: 0.000188 AC XY: 14AN XY: 74374
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 09, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 12, 2020 | Reported in two individuals of Italian ancestry with congenital glaucoma who were compound heterozygous for the P52L variant and another missense variant (Giuffre et al., 2011); Reported as a single heterozygous variant in two unrelated individuals, one with open angle glaucoma presenting at age 6, and the other with primary congenital glaucoma; however, this variant has also been observed in an older adult without visual defects, and in siblings and a parent of the patient with primary congenital glaucoma, leading some authors to suggest that this variant may demonstrate incomplete penetrance or that it may be rare variant unrelated to the phenotype (Lopez-Garrido, et al., 2006, Campos-Mollo et al., 2009; Pasutto et al., 2010); Published functional studies have demonstrated that P52L results in reduction but not absence of enzymatic activity as compared to wild-type, suggesting it may be a hypomorphic allele (Jeannot et al., 2007; Pasutto et al., 2010; Campos-Mollo et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31980526, 17363580, 27243976, 21815720, 16862072, 19234632, 30484747, 19643970) - |
Glaucoma, primary open angle, juvenile-onset Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2010 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 07, 2023 | Variant summary: CYP1B1 c.155C>T (p.Pro52Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 210080 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CYP1B1 causing Primary Congenital Glaucoma (0.00032 vs 0.0043), allowing no conclusion about variant significance. c.155C>T has been reported in the literature in several individuals affected with Primary Congenital Glaucoma and primary open angle glaucoma (e.g., Campos-Mollo_2009, Pasutto_2010, Giuffre_2011, Svidnicki_2018). However, the variant has also been reported in unaffected individuals, including a homozygous individual with epileptic encephalopathy but no evidence of anterior chamber ocular abnormality or glaucoma (e.g., Palmer_2016, Lopez-Garrido_2006). These reports suggest the variant represents a hypomorphic allele that may display incomplete penetrance, and therefore these reports do not provide unequivocal conclusions about association of the variant with Primary Congenital Glaucoma. Multiple publications also report experimental evidence evaluating an impact on protein function, finding that the variant protein displays drastically reduced enzymatic activity (ranging from ~0% to 40% of wild-type activity) as well as reduced protein stability (e.g., Jeannot_2007, Campos-Mollo_2009, Pasutto_2010, Lopez-Garrido_2010). The following publications have been ascertained in the context of this evaluation (PMID: 19234632, 21815720, 17363580, 19793111, 16862072, 27270415, 19643970, 30484747). Four ClinVar submitters (evaluation after 2014) have classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Irido-corneo-trabecular dysgenesis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Glaucoma 3A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Sift4G
Pathogenic
D;D;.
Vest4
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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