chr2-38071251-C-T

Variant names:

• chr2-38071251-C-T
• rs79204362
• NM_000104.4:c.1103G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 10P and 12B. PS3 PM1 PM5 PP2 PP3 BP4_Strong BS1 BS2

The NM_000104.4(CYP1B1):​c.1103G>A​(p.Arg368His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,613,104 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). ClinVar reports functional evidence for this variant: "SCV000914279: In vitro functional studies showed that the variant demonstrated reduced enzymatic activity (Pasutto et al. 2010" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R368L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (87 hom.)
• Consequence: CYP1B1 NM_000104.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:9 U:14 B:3 O:1
• Conservation: PhyloP100: 7.80
• Publications: 121 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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000914279: In vitro functional studies showed that the variant demonstrated reduced enzymatic activity (Pasutto et al. 2010; Mookherjee et al. 2012). Expression of the variant protein in E. coli resulted in approximately one-sixth of the amount of stable protein compared to wild type and severely reduced metabolism of all substrates tested (Choudhary et al. 2008).; SCV001020682: Experimental studies have shown that this missense change affects CYP1B1 function (PMID: 18622259, 19643970, 23028769, 27243976).; SCV001467890: Several publications report experimental evidence evaluating an impact on protein function, with the most pronounced variant effect resulting in <10% of normal activity (e.g. Choudhary_2008, Pasutto_2010, Mookherjee_2012, Banerjee_2016). PMID: 29556725, 27243976, 10655546, 18622259, 30788381, 38219857, 23028769, 19643970, 30653986, 19536304, 36239105.
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000104.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-38071252-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1489392.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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.
• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL [when AlphaMissense, max_spliceai, MetaRNN, MutationTaster, PrimateAI was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.009640098).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00202 (308/152310) while in subpopulation SAS AF = 0.0245 (118/4822). AF 95% confidence interval is 0.0209. There are 2 homozygotes in GnomAd4. There are 187 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1103G>A	p.Arg368His	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.1103G>A	p.Arg368His	missense	Exon 3 of 3	ENSP00000478561.1	Q16678
	CYP1B1	ENST00000490576.2	TSL:4	c.1103G>A	p.Arg368His	missense	Exon 3 of 3	ENSP00000478839.2	Q16678
	CYP1B1	ENST00000614273.1	TSL:5	c.1103G>A	p.Arg368His	missense	Exon 3 of 3	ENSP00000483678.1	Q16678

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 308 AN: 152192 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0245

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00582 AC: 1438 AN: 247034 AF XY: 0.00761

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00156

Gnomad OTH exome AF: 0.00593

GnomAD4 exome AF: 0.00323 AC: 4723 AN: 1460794 Hom.: 87 Cov.: 35 AF XY: 0.00430 AC XY: 3127 AN XY: 726720

African (AFR) AF: 0.000478 AC: 16 AN: 33480

American (AMR) AF: 0.00212 AC: 95 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 537 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0311 AC: 2686 AN: 86254

European-Finnish (FIN) AF: 0.0000764 AC: 4 AN: 52338

Middle Eastern (MID) AF: 0.0236 AC: 136 AN: 5768

European-Non Finnish (NFE) AF: 0.000897 AC: 997 AN: 1112008

Other (OTH) AF: 0.00414 AC: 250 AN: 60386

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152310 Hom.: 2 Cov.: 32 AF XY: 0.00251 AC XY: 187 AN XY: 74478

African (AFR) AF: 0.000481 AC: 20 AN: 41562

American (AMR) AF: 0.00118 AC: 18 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0245 AC: 118 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68034

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00222 Hom.: 5

Bravo AF: 0.00156

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00187 AC: 16

ExAC AF: 0.00596 AC: 721

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00279

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	6	1	Glaucoma 3A (11)
1	1	1	not provided (3)
1	1	-	CYP1B1-related disorder (2)
-	2	-	not specified (2)
-	1	-	Anterior segment dysgenesis 6 (1)
1	-	-	Congenital glaucoma (1)
-	1	-	Congenital ocular coloboma (1)
-	1	-	CYP1B1-related glaucoma with or without anterior segment dysgenesis (1)
-	-	1	Glaucoma 3, primary infantile, B;C1856439:Glaucoma 3A;C4310623:Anterior segment dysgenesis 6 (1)
1	-	-	Glaucoma, early-onset, digenic (1)
-	1	-	Myopathy, centronuclear, 5 (1)
1	-	-	Primary congenital glaucoma (1)
-	-	-	Irido-corneo-trabecular dysgenesis;C1856439:Glaucoma 3A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0096	T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.8
PrimateAI	Benign	0.42	T
Sift4G	Uncertain	0.010	D
Vest4		0.82
MVP		0.34
ClinPred		0.060	T
GERP RS		5.7
Varity_R		0.91
gMVP		0.82
Mutation Taster		=59/41	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: rs79204362; hg19: chr2-38298394; COSMIC: COSV52225428; COSMIC: COSV52225428;