Genetic Variant CYP1B1:c.*2333G>A (chr2-38068389-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000104.4(CYP1B1):c.*2333G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 227,722 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0024 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

CYP1B1
NM_000104.4 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -2.45

Publications

0 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 Gene-Disease associations (from GenCC):

CYP1B1-related glaucoma with or without anterior segment dysgenesis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
glaucoma 3A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
anterior segment dysgenesis 6
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
congenital glaucoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Peters anomaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CYP1B1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP1B1	NM_000104.4 link	c.*2333G>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000610745.5	NP_000095.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYP1B1	ENST00000610745.5 link	c.*2333G>A	3_prime_UTR_variant	Exon 3 of 3	1	NM_000104.4	ENSP00000478561.1	Q16678
CYP1B1	ENST00000490576.2 link	c.*2333G>A	3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000478839.2	A0A087WUQ7
CYP1B1	ENST00000714520.1 link	c.*2333G>A	3_prime_UTR_variant	Exon 3 of 3			ENSP00000519767.1
CYP1B1	ENST00000491456.1 link	n.184+789G>A	intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.00240

AC:

365

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00862

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:

0.0000294

Gnomad OTH

AF:

0.00144

GnomAD4 exome

AF:

0.000385

AC:

AN:

75418

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

34882

show subpopulations

African (AFR)

AF:

0.00710

AC:

AN:

3522

American (AMR)

AF:

0.000437

AC:

AN:

2286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4798

East Asian (EAS)

AF:

0.00

AC:

AN:

10792

South Asian (SAS)

AF:

0.00

AC:

AN:

648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

194

Middle Eastern (MID)

AF:

0.00216

AC:

AN:

462

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

46366

Other (OTH)

AF:

0.000315

AC:

AN:

6350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00242

AC:

369

AN:

152304

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00869

AC:

361

AN:

41554

American (AMR)

AF:

0.000196

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00126

Hom.:

Bravo

AF:

0.00268

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Irido-corneo-trabecular dysgenesis

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary congenital glaucoma

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.7

(source)

DANN

Benign

0.75

PhyloP100

-2.5

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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2-38068389-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over