Variant 2-38074520-C-CG details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000104.4(CYP1B1):c.868dupC(p.Arg290fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,608,236 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CYP1B1
NM_000104.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8U:1

Conservation

PhyloP100: 1.35

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:

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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 87 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-38074520-C-CG is Pathogenic according to our data. Variant chr2-38074520-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 68468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP1B1	NM_000104.4 linkuse as main transcript	c.868dupC	p.Arg290fs	frameshift_variant	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.868dupC	p.Arg290fs	frameshift_variant	2/3	1	NM_000104.4	ENSP00000478561.1		Q16678

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000258

AC:

AN:

232956

Hom.:

AF XY:

0.0000395

AC XY:

AN XY:

126728

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000341

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000482

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1456082

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

723902

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000770

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000468

Gnomad4 FIN exome

AF:

0.000133

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glaucoma 3A

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1997	- -
Pathogenic, no assertion criteria provided	research	Institute of Basic Medical Sciences, Khyber Medical University, Peshawar	Dec 06, 2023	A known frameshift homozygous mutation, c.868dupC was identified in CYP1B1 gene in Pakistani families. Later on, segregation studies also confirmed the mutation in other affected individuals in homozygous state while found in heterozygous pattern in parents and other normal siblings. All patients had uncontrollable IOP and bilateral corneal opacity with no perception of light. all the carriers of c.868dupC were phenotypically normal. Reference PMID: 30820150 -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2021	Frameshift 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: 30820150, 24281366, 25091052, 17893647, 17591938, 25018621, 9097971, 25950505, 31589614) -

Glaucoma 3A;C4310623:Anterior segment dysgenesis 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 20, 2024

- -

Anterior segment dysgenesis 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 25, 2024

- -

CYP1B1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 16, 2018

The CYP1B1 c.868dupC (p.Arg290ProfsTer37) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Arg290ProfsTer37 variant has been reported in at least five studies and is found in a total of 11 individuals from six families including ten in a homozygous state and one in a compound heterozygous state (Stoilov et al. 1997; Bagiyeva et al. 2007; Micheal et al. 2014; Prokudin et al. 2014; Souzeau et al. 2015). The compound heterozygous proband presented with iris and fundal colobomas and micropthalmia. Of note, the proband's mildly affected brother did not have the p.Arg290ProfsTer37 variant and therefore the variant's contribution to disease is difficult to ascertain in this family (Prokudin et al. 2014). One affected homozygous individual presented with juvenile open-angle glaucoma, not primary congenital glaucoma (Souzeau et al. 2015). The p.Arg290ProfsTer37 variant was absent from 690 controls and is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. Due to the potential impact of frameshift variants and the evidence in the literature, the p.Arg290ProfsTer37 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. -

Congenital glaucoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

This sequence change creates a premature translational stop signal (p.Arg290Profs*37) 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 (rs587778875, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with primary congenital glaucoma or juvenile open angle glaucoma (PMID: 9097971, 17591938, 25091052, 25950505). It has also been observed to segregate with disease in related individuals. This variant is also known as c.862insC and single cytosine base insertion (nt 1209- 1214). ClinVar contains an entry for this variant (Variation ID: 68468). For these reasons, this variant has been classified as Pathogenic. -

Congenital ocular coloboma

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Eye Genetics Research Group, Children's Medical Research Institute

Mar 30, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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