2-38075148-A-T

Variant names:

• chr2-38075148-A-T
• rs9282671
• NM_000104.4:c.241T>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PP2 PP3 BP4_Strong BP6 BS2

The NM_000104.4(CYP1B1):​c.241T>A​(p.Tyr81Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00391 in 1,574,856 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y81Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0040 (25 hom.)
• Consequence: CYP1B1 NM_000104.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:3
• Conservation: PhyloP100: 5.07
• Publications: 35 publications found

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-AS1 (HGNC:28543): (CYP1B1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -7 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.
• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, REVEL [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.010914177).
• BP6: Variant 2-38075148-A-T is Benign according to our data. Variant chr2-38075148-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 7744.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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.241T>A	p.Tyr81Asn	missense	Exon 2 of 3	NP_000095.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1B1	ENST00000610745.5	TSL:1 MANE Select	c.241T>A	p.Tyr81Asn	missense	Exon 2 of 3	ENSP00000478561.1
	CYP1B1	ENST00000490576.2	TSL:4	c.241T>A	p.Tyr81Asn	missense	Exon 2 of 3	ENSP00000478839.2
	CYP1B1	ENST00000614273.1	TSL:5	c.241T>A	p.Tyr81Asn	missense	Exon 2 of 3	ENSP00000483678.1

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 531 AN: 152176 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00456

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00355 AC: 654 AN: 183970 AF XY: 0.00381

Gnomad AFR exome AF: 0.000879

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00113

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0131

Gnomad NFE exome AF: 0.00451

Gnomad OTH exome AF: 0.00428

GnomAD4 exome AF: 0.00395 AC: 5622 AN: 1422562 Hom.: 25 Cov.: 35 AF XY: 0.00391 AC XY: 2757 AN XY: 705698

African (AFR) AF: 0.000726 AC: 24 AN: 33080

American (AMR) AF: 0.00188 AC: 77 AN: 40866

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 37 AN: 25606

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38452

South Asian (SAS) AF: 0.00277 AC: 231 AN: 83432

European-Finnish (FIN) AF: 0.0146 AC: 529 AN: 36240

Middle Eastern (MID) AF: 0.00161 AC: 9 AN: 5586

European-Non Finnish (NFE) AF: 0.00408 AC: 4484 AN: 1100054

Other (OTH) AF: 0.00388 AC: 230 AN: 59246

GnomAD4 genome AF: 0.00348 AC: 530 AN: 152294 Hom.: 3 Cov.: 34 AF XY: 0.00399 AC XY: 297 AN XY: 74480

African (AFR) AF: 0.000842 AC: 35 AN: 41566

American (AMR) AF: 0.00118 AC: 18 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4834

European-Finnish (FIN) AF: 0.0136 AC: 145 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00456 AC: 310 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00405 Hom.: 1

Bravo AF: 0.00250

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000729 AC: 3

ESP6500EA AF: 0.00411 AC: 34

ExAC AF: 0.00345 AC: 403

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Nov 30, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with primary congenital glaucoma, primary open-angle glaucoma, coloboma and micropthalmia, but many of these patients were not observed to harbor a second variant in CYP1B1, and Y81N did not segregate with disease in some families. (Melki et al., 2004; Mill et al., 2013; Prokudin et al., 2014; Reis et al., 2016; Rauf et al., 2016); Published functional studies demonstrate a reduction in enzyme activity compared to the wild type (Choudhary et al., 2008; Banerjee et al., 2016); This variant is associated with the following publications: (PMID: 19793111, 27508083, 22004014, 19204079, 19643970, 19234632, 27243976, 27820421, 25646030, 27777502, 23922489, 24281366, 16862072, 18470941, 15342693, 18622259)

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CYP1B1: PM3, PM2:Supporting, PS3:Supporting

Primary open angle glaucoma Pathogenic:1

Sep 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Anterior segment dysgenesis Uncertain:1

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as a VUS - 3A. 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 26550445, PMID: 10655546). (N) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to asparagine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (772 heterozygotes, 9 homozygotes). (N) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (2 heterozygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif, (p450 cytochrome domain; PDB, NCBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported as a VUS and benign, and observed in heterozygote controls or carriers with primary open-angle glaucoma (POAG) (ClinVar, LOVD, PMID: 27777502, PMID: 15342693). However more recently, this variant has been reported as pathogenic in homozygous and compound heterozygous patients with POAG and congenital glaucoma (PMID: 24281366, PMID: 27508083, PMID: 30520782, PMID: 22004014). (N) 1002 - Moderate functional evidence supporting abnormal protein function. Transfected cells demonstrated reduced protein expression (PMID: 18470941). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Irido-corneo-trabecular dysgenesis Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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

Aug 14, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Glaucoma 3A Benign:1

Apr 28, 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.

Congenital glaucoma Benign:1

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		5.1
PrimateAI	Uncertain	0.68	T
Sift4G	Pathogenic	0.0	D
Vest4		0.88
MVP		0.53
ClinPred		0.093	T
GERP RS		4.4
Varity_R		0.84
gMVP		0.93
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs9282671; hg19: chr2-38302291; COSMIC: COSV108073411; COSMIC: COSV108073411;