rs1056827

Variant names:

• chr2-38075034-C-A
• rs1056827
• NM_000104.4:c.355G>T
• CYP1B1 p.Ala119Ser

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000104.4(CYP1B1):​c.355G>T​(p.Ala119Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,588,118 control chromosomes in the GnomAD database, including 73,925 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). The gene CYP1B1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.35 (9842 hom., cov: 34)
  • Exomes 𝑓: 0.29 (64083 hom.)
• Consequence: CYP1B1 NM_000104.4 missense
• Clinical Significance: Benign reviewed by expert panel B:11
• Conservation: PhyloP100: -0.503
• Publications: 199 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

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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=1.7783786E-5).
• BP6: Variant 2-38075034-C-A is Benign according to our data. Variant chr2-38075034-C-A is described in ClinVar as Benign. ClinVar VariationId is 92437.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

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.355G>T	p.Ala119Ser	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.355G>T	p.Ala119Ser	missense	Exon 2 of 3	ENSP00000478561.1	Q16678
	CYP1B1	ENST00000490576.2	TSL:4	c.355G>T	p.Ala119Ser	missense	Exon 2 of 3	ENSP00000478839.2	Q16678
	CYP1B1	ENST00000614273.1	TSL:5	c.355G>T	p.Ala119Ser	missense	Exon 2 of 3	ENSP00000483678.1	Q16678

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52919 AN: 152028 Hom.: 9823 Cov.: 34

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.346

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.317

GnomAD2 exomes AF: 0.319 AC: 65208 AN: 204494 AF XY: 0.320

Gnomad AFR exome AF: 0.490

Gnomad AMR exome AF: 0.317

Gnomad ASJ exome AF: 0.234

Gnomad EAS exome AF: 0.196

Gnomad FIN exome AF: 0.366

Gnomad NFE exome AF: 0.303

Gnomad OTH exome AF: 0.310

GnomAD4 exome AF: 0.294 AC: 422171 AN: 1435970 Hom.: 64083 Cov.: 36 AF XY: 0.296 AC XY: 211668 AN XY: 713932

African (AFR) AF: 0.489 AC: 16279 AN: 33274

American (AMR) AF: 0.314 AC: 13665 AN: 43542

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 5992 AN: 25914

East Asian (EAS) AF: 0.150 AC: 5849 AN: 39110

South Asian (SAS) AF: 0.376 AC: 31936 AN: 84858

European-Finnish (FIN) AF: 0.360 AC: 13169 AN: 36604

Middle Eastern (MID) AF: 0.344 AC: 1968 AN: 5716

European-Non Finnish (NFE) AF: 0.285 AC: 315320 AN: 1107158

Other (OTH) AF: 0.301 AC: 17993 AN: 59794

GnomAD4 genome AF: 0.348 AC: 52986 AN: 152148 Hom.: 9842 Cov.: 34 AF XY: 0.352 AC XY: 26171 AN XY: 74386

African (AFR) AF: 0.474 AC: 19665 AN: 41530

American (AMR) AF: 0.320 AC: 4887 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 750 AN: 3470

East Asian (EAS) AF: 0.182 AC: 939 AN: 5166

South Asian (SAS) AF: 0.385 AC: 1860 AN: 4828

European-Finnish (FIN) AF: 0.365 AC: 3869 AN: 10606

Middle Eastern (MID) AF: 0.325 AC: 95 AN: 292

European-Non Finnish (NFE) AF: 0.291 AC: 19783 AN: 67944

Other (OTH) AF: 0.323 AC: 683 AN: 2114

Alfa AF: 0.298 Hom.: 5969

Bravo AF: 0.345

Asia WGS AF: 0.313 AC: 1089 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Glaucoma 3A (2)
-	-	2	not provided (2)
-	-	1	Anterior segment dysgenesis 6 (1)
-	-	1	Congenital glaucoma (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.7
DANN	Benign	0.83
DEOGEN2	Benign	0.069	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.000018	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-0.50
PrimateAI	Benign	0.28	T
Sift4G	Benign	0.16	T
Varity_R		0.053
gMVP		0.59
Mutation Taster		=99/1	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1056827;

hg19: chr2-38302177;

COSMIC: COSV53190557;

COSMIC: COSV53190557;