2-38070996-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000104.4(CYP1B1):c.1358A>G(p.Asn453Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,614,006 control chromosomes in the GnomAD database, including 25,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1623 hom., cov: 32)

Exomes 𝑓: 0.18 ( 24213 hom. )

Consequence

CYP1B1
NM_000104.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 7.91

Publications

244 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 -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 35 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Trascript score misZ: -2.0997 (below the threshold of 3.09). GenCC associations: The gene is linked to Peters anomaly, anterior segment dysgenesis 6, glaucoma 3A, CYP1B1-related glaucoma with or without anterior segment dysgenesis, congenital glaucoma.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016258061).

BP6

Variant 2-38070996-T-C is Benign according to our data. Variant chr2-38070996-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 166969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP1B1	NM_000104.4 link	c.1358A>G	p.Asn453Ser	missense_variant	Exon 3 of 3	ENST00000610745.5	NP_000095.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP1B1	ENST00000610745.5 link	c.1358A>G	p.Asn453Ser	missense_variant	Exon 3 of 3	1	NM_000104.4	ENSP00000478561.1

Frequencies

GnomAD3 genomes

AF:

0.130

AC:

19711

AN:

152108

Hom.:

1626

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0350

Gnomad AMI

AF:

0.0899

Gnomad AMR

AF:

0.134

Gnomad ASJ

AF:

0.163

Gnomad EAS

AF:

0.00462

Gnomad SAS

AF:

0.216

Gnomad FIN

AF:

0.148

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.184

Gnomad OTH

AF:

0.158

GnomAD2 exomes

AF:

0.153

AC:

38541

AN:

251460

AF XY:

0.164

show subpopulations

Gnomad AFR exome

AF:

0.0311

Gnomad AMR exome

AF:

0.114

Gnomad ASJ exome

AF:

0.166

Gnomad EAS exome

AF:

0.00337

Gnomad FIN exome

AF:

0.146

Gnomad NFE exome

AF:

0.186

Gnomad OTH exome

AF:

0.173

GnomAD4 exome

AF:

0.175

AC:

256523

AN:

1461780

Hom.:

24213

Cov.:

AF XY:

0.178

AC XY:

129501

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.0274

AC:

919

AN:

33480

American (AMR)

AF:

0.116

AC:

5180

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.163

AC:

4248

AN:

26136

East Asian (EAS)

AF:

0.00267

AC:

106

AN:

39700

South Asian (SAS)

AF:

0.229

AC:

19758

AN:

86256

European-Finnish (FIN)

AF:

0.146

AC:

7789

AN:

53420

Middle Eastern (MID)

AF:

0.184

AC:

1064

AN:

5768

European-Non Finnish (NFE)

AF:

0.186

AC:

207337

AN:

1111912

Other (OTH)

AF:

0.168

AC:

10122

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

12868

25735

38603

51470

64338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7088

14176

21264

28352

35440

<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:

0.129

AC:

19705

AN:

152226

Hom.:

1623

Cov.:

AF XY:

0.129

AC XY:

9579

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0349

AC:

1451

AN:

41538

American (AMR)

AF:

0.134

AC:

2044

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.163

AC:

564

AN:

3468

East Asian (EAS)

AF:

0.00463

AC:

AN:

5188

South Asian (SAS)

AF:

0.216

AC:

1043

AN:

4830

European-Finnish (FIN)

AF:

0.148

AC:

1568

AN:

10596

Middle Eastern (MID)

AF:

0.184

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.185

AC:

12547

AN:

67996

Other (OTH)

AF:

0.155

AC:

328

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

870

1740

2610

3480

4350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

240

480

720

960

1200

<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:

0.164

Hom.:

10559

Bravo

AF:

0.124

TwinsUK

AF:

0.191

AC:

710

ALSPAC

AF:

0.177

AC:

682

ESP6500AA

AF:

0.0334

AC:

147

ESP6500EA

AF:

0.187

AC:

1608

ExAC

AF:

0.155

AC:

18793

Asia WGS

AF:

0.0880

AC:

307

AN:

3478

EpiCase

AF:

0.191

EpiControl

AF:

0.196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15958554, 11854439, 15486049, 23861929, 10426814, 24604202) -

Oct 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glaucoma 3A

Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Anterior segment dysgenesis 6

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

May 12, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital glaucoma

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;T;T

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.82

.;T;D

MetaRNN

Benign

0.0016

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

M;.;M

PhyloP100

7.9

PrimateAI

Benign

0.29

Sift4G

Uncertain

0.0080

D;T;D

Vest4

0.089

ClinPred

0.012

GERP RS

6.0

Varity_R

0.30

gMVP

0.82

Mutation Taster

=95/5

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over