rs777678299

Variant names:

• chr2-38074404-C-T
• rs777678299
• NM_000104.4:c.985G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP2 PP3_Moderate PP5_Very_Strong

The NM_000104.4(CYP1B1):​c.985G>A​(p.Gly329Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G329G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CYP1B1 NM_000104.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 5.62
• Publications: 7 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-AS1 (HGNC:28543): (CYP1B1 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• 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, 0.921
• PP5: Variant 2-38074404-C-T is Pathogenic according to our data. Variant chr2-38074404-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 632362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.985G>A	p.Gly329Ser	missense	Exon 2 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.985G>A	p.Gly329Ser	missense	Exon 2 of 3	ENSP00000478561.1	Q16678
	CYP1B1	ENST00000490576.2	TSL:4	c.985G>A	p.Gly329Ser	missense	Exon 2 of 3	ENSP00000478839.2	Q16678
	CYP1B1	ENST00000614273.1	TSL:5	c.985G>A	p.Gly329Ser	missense	Exon 2 of 3	ENSP00000483678.1	Q16678

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248888 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461098 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 726850

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111946

Other (OTH) AF: 0.0000497 AC: 3 AN: 60366

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Anterior segment dysgenesis 6 (1)
1	-	-	Congenital glaucoma (1)
-	1	-	CYP1B1-related glaucoma with or without anterior segment dysgenesis (1)
1	-	-	Glaucoma 3A (1)
1	-	-	Primary congenital glaucoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.6
PrimateAI	Uncertain	0.77	T
Sift4G	Benign	0.069	T
Vest4		0.94
MVP		0.44
ClinPred		0.94	D
GERP RS		4.0
Varity_R		0.87
gMVP		0.78
Mutation Taster		=12/88	disease causing (ClinVar)

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: rs777678299; hg19: chr2-38301547;