rs2855658

Variant names:

• chr2-38069747-T-C
• rs2855658
• NM_000104.4:c.*975A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000104.4(CYP1B1):​c.*975A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.531 in 197,520 control chromosomes in the GnomAD database, including 31,322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (22357 hom., cov: 31)
  • Exomes 𝑓: 0.61 (8965 hom.)
• Consequence: CYP1B1 NM_000104.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.452
• Publications: 30 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 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-38069747-T-C is Benign according to our data. Variant chr2-38069747-T-C is described in ClinVar as Benign. ClinVar VariationId is 335936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP1B1	NM_000104.4	c.*975A>G		3_prime_UTR_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	c.*975A>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_000104.4	ENSP00000478561.1
CYP1B1	ENST00000490576.2	c.*975A>G		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000478839.2
CYP1B1	ENST00000714520.1	c.*975A>G		3_prime_UTR_variant	Exon 3 of 3			ENSP00000519767.1
CYP1B1	ENST00000491456.1	n.89-474A>G		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77140 AN: 151864 Hom.: 22361 Cov.: 31

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.678

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.889

Gnomad SAS AF: 0.808

Gnomad FIN AF: 0.642

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.566

Gnomad OTH AF: 0.554

GnomAD4 exome AF: 0.609 AC: 27717 AN: 45536 Hom.: 8965 Cov.: 0 AF XY: 0.609 AC XY: 12910 AN XY: 21214

African (AFR) AF: 0.223 AC: 438 AN: 1960

American (AMR) AF: 0.685 AC: 876 AN: 1278

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1474 AN: 2908

East Asian (EAS) AF: 0.865 AC: 6432 AN: 7440

South Asian (SAS) AF: 0.815 AC: 318 AN: 390

European-Finnish (FIN) AF: 0.714 AC: 20 AN: 28

Middle Eastern (MID) AF: 0.683 AC: 190 AN: 278

European-Non Finnish (NFE) AF: 0.574 AC: 15759 AN: 27474

Other (OTH) AF: 0.585 AC: 2210 AN: 3780

GnomAD4 genome AF: 0.508 AC: 77151 AN: 151984 Hom.: 22357 Cov.: 31 AF XY: 0.522 AC XY: 38757 AN XY: 74294

African (AFR) AF: 0.228 AC: 9463 AN: 41476

American (AMR) AF: 0.678 AC: 10349 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1722 AN: 3462

East Asian (EAS) AF: 0.889 AC: 4600 AN: 5176

South Asian (SAS) AF: 0.808 AC: 3903 AN: 4830

European-Finnish (FIN) AF: 0.642 AC: 6749 AN: 10520

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.566 AC: 38436 AN: 67934

Other (OTH) AF: 0.557 AC: 1174 AN: 2108

Alfa AF: 0.542 Hom.: 54402

Bravo AF: 0.497

Asia WGS AF: 0.797 AC: 2766 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glaucoma 3A Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Irido-corneo-trabecular dysgenesis Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.9
DANN	Benign	0.62
PhyloP100		-0.45
Mutation Taster		=99/1	polymorphism (auto)

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: rs2855658; hg19: chr2-38296890;