2-38070372-G-T

Variant names:

• chr2-38070372-G-T
• rs162562
• NM_000104.4:c.*350C>A

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.*350C>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 0.736 in 317,726 control chromosomes in the GnomAD database, including 89,900 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (38398 hom., cov: 33)
  • Exomes 𝑓: 0.78 (51502 hom.)
• Consequence: CYP1B1 NM_000104.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.288
• Publications: 25 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=-0.9).
• BP6: Variant 2-38070372-G-T is Benign according to our data. Variant chr2-38070372-G-T is described in ClinVar as Benign. ClinVar VariationId is 335944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

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.*350C>A		3_prime_UTR	Exon 3 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.*350C>A		3_prime_UTR	Exon 3 of 3	ENSP00000478561.1
	CYP1B1	ENST00000490576.2	TSL:4	c.*350C>A		3_prime_UTR	Exon 3 of 3	ENSP00000478839.2
	CYP1B1	ENST00000714520.1		c.*350C>A		3_prime_UTR	Exon 3 of 3	ENSP00000519767.1

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104427 AN: 151962 Hom.: 38405 Cov.: 33

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.692

Gnomad AMR AF: 0.845

Gnomad ASJ AF: 0.727

Gnomad EAS AF: 0.905

Gnomad SAS AF: 0.906

Gnomad FIN AF: 0.765

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.774

Gnomad OTH AF: 0.756

GnomAD4 exome AF: 0.781 AC: 129450 AN: 165646 Hom.: 51502 Cov.: 0 AF XY: 0.789 AC XY: 64658 AN XY: 81986

African (AFR) AF: 0.391 AC: 2736 AN: 7002

American (AMR) AF: 0.862 AC: 5777 AN: 6698

Ashkenazi Jewish (ASJ) AF: 0.746 AC: 5296 AN: 7098

East Asian (EAS) AF: 0.888 AC: 13897 AN: 15646

South Asian (SAS) AF: 0.903 AC: 10513 AN: 11644

European-Finnish (FIN) AF: 0.761 AC: 2694 AN: 3538

Middle Eastern (MID) AF: 0.863 AC: 640 AN: 742

European-Non Finnish (NFE) AF: 0.776 AC: 79442 AN: 102368

Other (OTH) AF: 0.775 AC: 8455 AN: 10910

GnomAD4 genome AF: 0.687 AC: 104459 AN: 152080 Hom.: 38398 Cov.: 33 AF XY: 0.694 AC XY: 51636 AN XY: 74372

African (AFR) AF: 0.404 AC: 16734 AN: 41418

American (AMR) AF: 0.845 AC: 12920 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.727 AC: 2524 AN: 3472

East Asian (EAS) AF: 0.904 AC: 4683 AN: 5178

South Asian (SAS) AF: 0.906 AC: 4374 AN: 4828

European-Finnish (FIN) AF: 0.765 AC: 8103 AN: 10588

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.774 AC: 52647 AN: 67986

Other (OTH) AF: 0.756 AC: 1595 AN: 2110

Alfa AF: 0.754 Hom.: 174843

Bravo AF: 0.681

Asia WGS AF: 0.868 AC: 3020 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glaucoma 3A Benign:1

Jan 13, 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 13, 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.51
PhyloP100		-0.29
Mutation Taster		=100/0	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: rs162562; hg19: chr2-38297515;