2-38074704-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_000104.4(CYP1B1):c.685G>A(p.Glu229Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0083 in 1,612,244 control chromosomes in the GnomAD database, including 195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★).

Frequency

Genomes: 𝑓 0.0062 ( 14 hom., cov: 33)

Exomes 𝑓: 0.0085 ( 181 hom. )

Consequence

CYP1B1
NM_000104.4 missense

Scores

Clinical Significance

Benign/Likely benign; other criteria provided, multiple submitters, no conflicts U:1B:6O:1

Conservation

PhyloP100: 2.67

Publications

81 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: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000104.4

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=0.004917532).

BP6

Variant 2-38074704-C-T is Benign according to our data. Variant chr2-38074704-C-T is described in ClinVar as Benign/Likely_benign|other. ClinVar VariationId is 68467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP1B1	NM_000104.4 link	c.685G>A	p.Glu229Lys	missense_variant	Exon 2 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.685G>A	p.Glu229Lys	missense_variant	Exon 2 of 3	1	NM_000104.4	ENSP00000478561.1

Frequencies

GnomAD3 genomes

AF:

0.00621

AC:

946

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0505

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00779

Gnomad OTH

AF:

0.00764

GnomAD2 exomes

AF:

0.0109

AC:

2661

AN:

243382

AF XY:

0.0137

show subpopulations

Gnomad AFR exome

AF:

0.000929

Gnomad AMR exome

AF:

0.00187

Gnomad ASJ exome

AF:

0.0105

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00308

Gnomad NFE exome

AF:

0.00795

Gnomad OTH exome

AF:

0.00708

GnomAD4 exome

AF:

0.00852

AC:

12443

AN:

1459864

Hom.:

181

Cov.:

AF XY:

0.0101

AC XY:

7329

AN XY:

726148

show subpopulations

African (AFR)

AF:

0.000956

AC:

AN:

33458

American (AMR)

AF:

0.00206

AC:

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

264

AN:

26070

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39674

South Asian (SAS)

AF:

0.0518

AC:

4458

AN:

85984

European-Finnish (FIN)

AF:

0.00261

AC:

136

AN:

52202

Middle Eastern (MID)

AF:

0.0206

AC:

119

AN:

5766

European-Non Finnish (NFE)

AF:

0.00613

AC:

6812

AN:

1111770

Other (OTH)

AF:

0.00875

AC:

528

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

899

1798

2696

3595

4494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

268

536

804

1072

1340

<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:

0.00620

AC:

945

AN:

152380

Hom.:

Cov.:

AF XY:

0.00691

AC XY:

515

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.000817

AC:

AN:

41592

American (AMR)

AF:

0.00340

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0503

AC:

243

AN:

4832

European-Finnish (FIN)

AF:

0.00226

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00779

AC:

530

AN:

68036

Other (OTH)

AF:

0.00756

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

133

177

221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00741

Hom.:

Bravo

AF:

0.00443

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.0120

AC:

1454

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.00862

EpiControl

AF:

0.00945

ClinVar

Significance: Benign/Likely benign; other

Submissions summary: Uncertain:1Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glaucoma 3A

Benign:2

Jun 12, 2024

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

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. -

not provided

Benign:1Other:1

Mar 24, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15037581, 19643970, 28620713, 32153331, 30270463, 30108387, 29168043, 25091052, 16862072, 26517685, 28386709, 18470941, 25261878, 27777502, 27884173, 27243976, 11558822, 23028769, 18622259, 19234632, 19236111, 19793111, 22004014, 25527694, 27508083) -

Aug 11, 2014

Eurofins Ntd Llc (ga)

Significance:other

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

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

- -

not specified

Benign:1

Dec 10, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Irido-corneo-trabecular dysgenesis

Benign:1

Aug 22, 2023

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital glaucoma

Benign:1

Jan 22, 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

0.30

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;T

Eigen

Benign

0.14

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.93

.;D

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.6

L;L

PhyloP100

2.7

PrimateAI

Uncertain

0.60

Sift4G

Benign

0.12

T;T

Vest4

0.70

ClinPred

0.026

GERP RS

3.8

Varity_R

0.62

gMVP

0.58

Mutation Taster

=98/2

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