chr2-38074704-C-T

Variant names:

• chr2-38074704-C-T
• rs57865060
• NM_000104.4:c.685G>A

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.685G>A​(p.Glu229Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0083 in 1,612,244 control chromosomes in the GnomAD database, including 195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0085 (181 hom.)
• Consequence: CYP1B1 NM_000104.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:7 O:1
• Conservation: PhyloP100: 2.67
• Publications: 81 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: 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 0 benign, 3 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 Peters anomaly, anterior segment dysgenesis 6, glaucoma 3A, CYP1B1-related glaucoma with or without anterior segment dysgenesis, congenital glaucoma.
• BP4: Computational evidence support a benign effect (MetaRNN=0.004917532).
• BP6: Variant 2-38074704-C-T is Benign according to our data. Variant chr2-38074704-C-T is described in ClinVar as Benign/Likely_benign|other. ClinVar VariationId is 68467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0506 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.685G>A	p.Glu229Lys	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.685G>A	p.Glu229Lys	missense	Exon 2 of 3	ENSP00000478561.1	Q16678
	CYP1B1	ENST00000490576.2	TSL:4	c.685G>A	p.Glu229Lys	missense	Exon 2 of 3	ENSP00000478839.2	Q16678
	CYP1B1	ENST00000614273.1	TSL:5	c.685G>A	p.Glu229Lys	missense	Exon 2 of 3	ENSP00000483678.1	Q16678

Frequencies

GnomAD3 genomes AF: 0.00621 AC: 946 AN: 152264 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0505

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00779

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.0109 AC: 2661 AN: 243382 AF XY: 0.0137

Gnomad AFR exome AF: 0.000929

Gnomad AMR exome AF: 0.00187

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00308

Gnomad NFE exome AF: 0.00795

Gnomad OTH exome AF: 0.00708

GnomAD4 exome AF: 0.00852 AC: 12443 AN: 1459864 Hom.: 181 Cov.: 31 AF XY: 0.0101 AC XY: 7329 AN XY: 726148

African (AFR) AF: 0.000956 AC: 32 AN: 33458

American (AMR) AF: 0.00206 AC: 92 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 264 AN: 26070

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39674

South Asian (SAS) AF: 0.0518 AC: 4458 AN: 85984

European-Finnish (FIN) AF: 0.00261 AC: 136 AN: 52202

Middle Eastern (MID) AF: 0.0206 AC: 119 AN: 5766

European-Non Finnish (NFE) AF: 0.00613 AC: 6812 AN: 1111770

Other (OTH) AF: 0.00875 AC: 528 AN: 60322

GnomAD4 genome AF: 0.00620 AC: 945 AN: 152380 Hom.: 14 Cov.: 33 AF XY: 0.00691 AC XY: 515 AN XY: 74516

African (AFR) AF: 0.000817 AC: 34 AN: 41592

American (AMR) AF: 0.00340 AC: 52 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0503 AC: 243 AN: 4832

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10632

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

European-Non Finnish (NFE) AF: 0.00779 AC: 530 AN: 68036

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00741 Hom.: 10

Bravo AF: 0.00443

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.0120 AC: 1454

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.00862

EpiControl AF: 0.00945

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.7
PrimateAI	Uncertain	0.60	T
Sift4G	Benign	0.12	T
Vest4		0.70
ClinPred		0.026	T
GERP RS		3.8
Varity_R		0.62
gMVP		0.58
Mutation Taster		=98/2	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

Other links and lift over

dbSNP: rs57865060; hg19: chr2-38301847;