chr2-38074520-C-CG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000104.4(CYP1B1):c.868dupC(p.Arg290ProfsTer37) 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 (★★). Variant results in nonsense mediated mRNA decay.

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:9U:1

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

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

PP5

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000104.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1B1	NM_000104.4	MANE Select	c.868dupC	p.Arg290ProfsTer37	frameshift	Exon 2 of 3	NP_000095.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CYP1B1	ENST00000610745.5	TSL:1 MANE Select	c.868dupC	p.Arg290ProfsTer37	frameshift	Exon 2 of 3	ENSP00000478561.1
CYP1B1	ENST00000490576.2	TSL:4	c.868dupC	p.Arg290ProfsTer37	frameshift	Exon 2 of 3	ENSP00000478839.2
CYP1B1	ENST00000614273.1	TSL:5	c.868dupC	p.Arg290ProfsTer37	frameshift	Exon 2 of 3	ENSP00000483678.1

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

GnomAD2 exomes

AF:

0.0000258

AC:

AN:

232956

AF XY:

0.0000395

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 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

African (AFR)

AF:

0.00

AC:

AN:

33434

American (AMR)

AF:

0.00

AC:

AN:

43628

Ashkenazi Jewish (ASJ)

AF:

0.0000770

AC:

AN:

25962

East Asian (EAS)

AF:

0.00

AC:

AN:

39482

South Asian (SAS)

AF:

0.0000468

AC:

AN:

85454

European-Finnish (FIN)

AF:

0.000133

AC:

AN:

52572

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1109638

Other (OTH)

AF:

0.0000166

AC:

AN:

60154

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Apr 12, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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)

Feb 07, 2018

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 25, 2024

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Glaucoma 3A

Pathogenic:2

Dec 06, 2023

Institute of Basic Medical Sciences, Khyber Medical University, Peshawar

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

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

Apr 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Glaucoma 3A;C4310623:Anterior segment dysgenesis 6

Pathogenic:1

Apr 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Anterior segment dysgenesis 6

Pathogenic:1

Feb 25, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CYP1B1-related disorder

Pathogenic:1

Oct 16, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Dec 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Mar 30, 2012

Eye Genetics Research Group, Children's Medical Research Institute

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over