2-38075218-C-T

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.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 (★★). Variant results in nonsense mediated mRNA decay.

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 reviewed by expert panel P:16

Conservation

PhyloP100: 3.28

Publications

33 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 2-38075218-C-T is Pathogenic according to our data. Variant chr2-38075218-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 7737.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1B1	NM_000104.4	MANE Select	c.171G>A	p.Trp57*	stop_gained	Exon 2 of 3	NP_000095.2	Q16678

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP1B1	ENST00000610745.5	TSL:1 MANE Select	c.171G>A	p.Trp57*	stop_gained	Exon 2 of 3	ENSP00000478561.1	Q16678
CYP1B1	ENST00000490576.2	TSL:4	c.171G>A	p.Trp57*	stop_gained	Exon 2 of 3	ENSP00000478839.2	Q16678
CYP1B1	ENST00000614273.1	TSL:5	c.171G>A	p.Trp57*	stop_gained	Exon 2 of 3	ENSP00000483678.1	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

GnomAD2 exomes

AF:

0.000173

AC:

AN:

201850

AF XY:

0.000181

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 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

African (AFR)

AF:

0.000120

AC:

AN:

33216

American (AMR)

AF:

0.0000242

AC:

AN:

41310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25612

East Asian (EAS)

AF:

0.0000513

AC:

AN:

38984

South Asian (SAS)

AF:

0.00

AC:

AN:

83942

European-Finnish (FIN)

AF:

0.0000249

AC:

AN:

40232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4960

European-Non Finnish (NFE)

AF:

0.000526

AC:

580

AN:

1102742

Other (OTH)

AF:

0.000151

AC:

AN:

59470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

124

166

207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<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:

0.000243

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41474

American (AMR)

AF:

0.000196

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68044

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000957

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

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Anterior segment dysgenesis 6 (3)

not provided (3)

CYP1B1-related disorder (2)

Glaucoma 3A (2)

Anterior segment dysgenesis (1)

Congenital glaucoma (1)

CYP1B1-related glaucoma with or without anterior segment dysgenesis (1)

Glaucoma 3, primary infantile, B;C1856439:Glaucoma 3A;C4310623:Anterior segment dysgenesis 6 (1)

Glaucoma 3A;C4310623:Anterior segment dysgenesis 6 (1)

Irido-corneo-trabecular dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.91

PhyloP100

3.3

Vest4

0.76

GERP RS

4.2

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

Computational scores

Splicing

Publications

Other links and lift over