2-38074398-TGGCGCCGAA-T

Position:

• chr2-38074398-TGGCGCCGAA-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP5_Moderate

The ENST00000610745.5(CYP1B1):​c.982_990del​(p.Phe328_Ala330del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYP1B1 ENST00000610745.5 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.46

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

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in ENST00000610745.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000610745.5.
• PP5: Variant 2-38074398-TGGCGCCGAA-T is Pathogenic according to our data. Variant chr2-38074398-TGGCGCCGAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 2827579.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP1B1	NM_000104.4	c.982_990del	p.Phe328_Ala330del	inframe_deletion	2/3	ENST00000610745.5	NP_000095.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP1B1	ENST00000610745.5	c.982_990del	p.Phe328_Ala330del	inframe_deletion	2/3	1	NM_000104.4	ENSP00000478561	P1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital glaucoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2023

This variant is not present in population databases (gnomAD no frequency). This variant, c.982_990del, results in the deletion of 3 amino acid(s) of the CYP1B1 protein (p.Phe328_Ala330del), but otherwise preserves the integrity of the reading frame. This variant has not been reported in the literature in individuals affected with CYP1B1-related conditions. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CYP1B1 protein in which other variant(s) (p.Gly329Ser) have been determined to be pathogenic (PMID: 17363580, 22942166, 27243976). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-38301541;