rs1064792896

Variant names:

• chr2-38071278-TCTGCCTGCACTCG-T
• rs1064792896
• NM_000104.4:c.1063_1075delCGAGTGCAGGCAG

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_000104.4(CYP1B1):​c.1063_1075delCGAGTGCAGGCAG​(p.Arg355AsnfsTer69) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars). The gene CYP1B1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP1B1 NM_000104.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.86
• Publications: 0 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: Ambry Genetics, ClinGen
• glaucoma 3A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• congenital glaucoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Peters anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for CYP1B1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 49 pathogenic variants in the truncated region.
• PP5: Variant 2-38071278-TCTGCCTGCACTCG-T is Pathogenic according to our data. Variant chr2-38071278-TCTGCCTGCACTCG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 417858.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1B1	NM_000104.4	MANE Select	c.1063_1075delCGAGTGCAGGCAG	p.Arg355AsnfsTer69	frameshift	Exon 3 of 3	NP_000095.2	Q16678

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1B1	ENST00000610745.5	TSL:1 MANE Select	c.1063_1075delCGAGTGCAGGCAG	p.Arg355AsnfsTer69	frameshift	Exon 3 of 3	ENSP00000478561.1	Q16678
	CYP1B1	ENST00000490576.2	TSL:4	c.1063_1075delCGAGTGCAGGCAG	p.Arg355AsnfsTer69	frameshift	Exon 3 of 3	ENSP00000478839.2	Q16678
	CYP1B1	ENST00000614273.1	TSL:5	c.1063_1075delCGAGTGCAGGCAG	p.Arg355AsnfsTer69	frameshift	Exon 3 of 3	ENSP00000483678.1	Q16678

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Irido-corneo-trabecular dysgenesis;C1856439:Glaucoma 3A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1064792896; hg19: chr2-38298421;