rs4986888

Variant names:

• chr2-38071026-G-C
• rs4986888
• NM_000104.4:c.1328C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-38071026-G-C
• chr2-38071026-G-A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000104.4(CYP1B1):​c.1328C>G​(p.Ala443Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00331 in 1,614,070 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). The gene CYP1B1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.015 (47 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (39 hom.)
• Consequence: CYP1B1 NM_000104.4 missense
• Clinical Significance: Likely benign reviewed by expert panel B:8
• Conservation: PhyloP100: 1.05
• Publications: 38 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: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000104.4
• 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 congenital glaucoma, glaucoma 3A, CYP1B1-related glaucoma with or without anterior segment dysgenesis, Peters anomaly.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0049704313).
• BP6: Variant 2-38071026-G-C is Benign according to our data. Variant chr2-38071026-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 92435.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0149 (2276/152252) while in subpopulation AFR AF = 0.0487 (2022/41532). AF 95% confidence interval is 0.0469. There are 47 homozygotes in GnomAd4. There are 1089 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 47 AD,AR gene

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.1328C>G	p.Ala443Gly	missense	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.1328C>G	p.Ala443Gly	missense	Exon 3 of 3	ENSP00000478561.1	Q16678
	CYP1B1	ENST00000490576.2	TSL:4	c.1328C>G	p.Ala443Gly	missense	Exon 3 of 3	ENSP00000478839.2	Q16678
	CYP1B1	ENST00000614273.1	TSL:5	c.1328C>G	p.Ala443Gly	missense	Exon 3 of 3	ENSP00000483678.1	Q16678

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2265 AN: 152134 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.0485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00838

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00439 AC: 1105 AN: 251448 AF XY: 0.00333

Gnomad AFR exome AF: 0.0474

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.00476

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.000932

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00210 AC: 3065 AN: 1461818 Hom.: 39 Cov.: 52 AF XY: 0.00193 AC XY: 1406 AN XY: 727208

African (AFR) AF: 0.0508 AC: 1701 AN: 33480

American (AMR) AF: 0.00450 AC: 201 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00348 AC: 91 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86250

European-Finnish (FIN) AF: 0.000449 AC: 24 AN: 53416

Middle Eastern (MID) AF: 0.00867 AC: 50 AN: 5766

European-Non Finnish (NFE) AF: 0.000617 AC: 686 AN: 1111974

Other (OTH) AF: 0.00475 AC: 287 AN: 60388

GnomAD4 genome AF: 0.0149 AC: 2276 AN: 152252 Hom.: 47 Cov.: 33 AF XY: 0.0146 AC XY: 1089 AN XY: 74426

African (AFR) AF: 0.0487 AC: 2022 AN: 41532

American (AMR) AF: 0.00830 AC: 127 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000661 AC: 7 AN: 10592

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 68032

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.00178 Hom.: 2

Bravo AF: 0.0172

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0517 AC: 228

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00528 AC: 641

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00142

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Congenital glaucoma (1)
-	-	1	CYP1B1-related glaucoma with or without anterior segment dysgenesis (1)
-	-	1	Glaucoma 3A (1)
-	-	1	Irido-corneo-trabecular dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N
PhyloP100		1.1
PrimateAI	Benign	0.22	T
Sift4G	Benign	0.29	T
Vest4		0.042
MVP		0.13
ClinPred		0.00063	T
GERP RS		4.2
Varity_R		0.11
gMVP		0.68
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs4986888; hg19: chr2-38298169; COSMIC: COSV99029601; COSMIC: COSV99029601;