rs147535955

Variant names:

• chr2-38070942-A-C
• rs147535955
• NM_000104.4:c.1412T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-38070942-A-C
• chr2-38070942-A-G
• chr2-38070942-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_000104.4(CYP1B1):​c.1412T>G​(p.Ile471Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I471N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP1B1 NM_000104.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.20
• Publications: 3 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000104.4
• PM2: Very rare variant in population databases, with high coverage
• 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: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant 2-38070942-A-C is Pathogenic according to our data. Variant chr2-38070942-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3251434.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP1B1	NM_000104.4	c.1412T>G	p.Ile471Ser	missense_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.1412T>G	p.Ile471Ser	missense_variant	Exon 3 of 3	1	NM_000104.4	ENSP00000478561.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary congenital glaucoma Pathogenic:1

Apr 08, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CYP1B1 c.1412T>G (p.Ile471Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251478 control chromosomes. c.1412T>G has been reported in the literature in individuals affected with Primary Congenital Glaucoma. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29540704, 19247456). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;T;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.2	M;.;M
PhyloP100		9.2
PrimateAI	Benign	0.48	T
Sift4G	Uncertain	0.0030	D;T;D
Vest4		0.77
MVP		0.71
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.82
gMVP		0.93
Mutation Taster		=25/75	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: rs147535955; hg19: chr2-38298085;