2-38075218-C-T

Position:

chr2-38075218-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000104.4(CYP1B1):c.171G>A(p.Trp57*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,582,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00042 ( 0 hom. )

Consequence

CYP1B1
NM_000104.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 3.28

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 (HGNC:):

CYP1B1 links:

Genome browser will be placed here

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 167 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-38075218-C-T is Pathogenic according to our data. Variant chr2-38075218-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-38075218-C-T is described in Lovd as [Pathogenic]. Variant chr2-38075218-C-T is described in Lovd as [Likely_pathogenic]. Variant chr2-38075218-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP1B1	NM_000104.4 linkuse as main transcript	c.171G>A	p.Trp57*	stop_gained	2/3	ENST00000610745.5	NP_000095.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP1B1	ENST00000610745.5 linkuse as main transcript	c.171G>A	p.Trp57*	stop_gained	2/3	1	NM_000104.4	ENSP00000478561.1		Q16678

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000173

AC:

AN:

201850

Hom.:

AF XY:

0.000181

AC XY:

AN XY:

110788

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000330

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000374

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000417

AC:

597

AN:

1430468

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

277

AN XY:

709858

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000242

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000513

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000249

Gnomad4 NFE exome

AF:

0.000526

Gnomad4 OTH exome

AF:

0.000151

GnomAD4 genome

AF:

0.000243

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000341

Hom.:

Bravo

AF:

0.000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000465

AC:

ESP6500EA

AF:

0.000237

AC:

ExAC

AF:

0.000194

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Anterior segment dysgenesis 6

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Aug 25, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 14635112, 11403040, 16735994, 30653986, 23218701, 24281366, 27820421, 34758253, 12525557, 19643970, 17718864, 23922489, 27777502, 12036985, 26689913, 31980526, 31589614, 32499604, 22004014, 35170016) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 16, 2020	- -

Glaucoma 3A

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2013	The Trp57X variant in CYP1B1 has been previously identified in 1 compound heterozygous individual with Peter's anomaly and secondary congenital glaucoma (Vincent 2001), in 1 heterozygous individual with primary open angle glaucoma (Pasutto 2010), in 1 heterozygous patient with pseudoexfoliative glaucoma (Patel 2012), and was found to segregate with disease in 1 affected relative with primary open angle glaucoma (Patel 2012). This variant has been identified in 2/8428 of European American chromosomes and 2/4298 of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs72549387). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 57, which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic in a recessive manner for primary congenital glaucoma. In addition, one study reported an association between carrier status for pathogenic CYP1B1 variants and risk for adult-onset primary open angle glaucoma (Pasutto 2010). However, this study has not been replicated. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

CYP1B1-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The CYP1B1 c.171G>A (p.Trp57Ter) variant is a stop-gained variant. Across a selection of the available literature, the p.Trp57Ter variant has been reported in at least seven studies in which it was found in a compound heterozygous state in four individuals with Peters anomaly and six individuals with primary congenital glaucoma (including one set of twins), and in a heterozygous state in one individual with pseudoexfoliative glaucoma and two individuals with with juvenile open angle glaucoma, both of whom carried additional variants in another gene. The variant was also reported in a heterozygous state in three unaffected individuals (Vincent et al. 2001; Stoilov et al. 2002; Pasutto et al. 2010; Patel et al. 2012; Lim et al. 2013; Milla et al. 2013; Prokudin et al. 2014). The p.Trp57Ter variant was found in a heterozygous state in three of 1190 control alleles and is reported at a frequency of 0.00072 in the European (non-Finnish) population of the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants and the collective evidence, the p.Trp57Ter variant is classified as pathogenic for CYP1B1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 17, 2024	The CYP1B1 c.171G>A variant is predicted to result in premature protein termination (p.Trp57*). This variant has been reported in the compound heterozygous state in individuals with Peter's anomaly or congenital glaucoma (Vincent et al. 2001. PubMed ID: 11403040; Prokudin et al. 2013. PubMed ID: 24281366; Grønskov et al 2016. PubMed ID: 27820421; Millá et al. 2013. PubMed ID: 23922489), and in the heterozygous state in individuals with primary open angle glaucoma (Pasutto et al. 2010. PubMed ID: 19643970; Patel et al. 2012. PubMed ID: 22004014). This variant is reported in 0.039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in CYP1B1 are expected to be pathogenic. Given the evidence, this variant is interpreted as pathogenic for autosomal recessive disease; additionally this variant may confer a risk for the development of primary open angle glaucoma. -

Anterior segment dysgenesis

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Eye Genetics Research Group, Children's Medical Research Institute

Mar 31, 2020

- -

Glaucoma 3, primary infantile, B;C1856439:Glaucoma 3A;C4310623:Anterior segment dysgenesis 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Irido-corneo-trabecular dysgenesis

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Eye Genetics Research Group, Children's Medical Research Institute

Mar 30, 2012

- -

Congenital glaucoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change creates a premature translational stop signal (p.Trp57*) 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). This variant is present in population databases (rs72549387, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with primary congenital glaucoma and primary open angle glaucoma and Peter's anomaly (PMID: 11403040, 12036985, 19643970, 22004014, 23218701, 23922489, 24281366, 27820421). ClinVar contains an entry for this variant (Variation ID: 7737). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.91

Vest4

0.76

GERP RS

4.2

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over