rs1056836

Variant names:

• chr2-38071060-G-C
• rs1056836
• NM_000104.4:c.1294C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-38071060-G-C
• chr2-38071060-G-A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000104.4(CYP1B1):​c.1294C>G​(p.Leu432Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 1,613,386 control chromosomes in the GnomAD database, including 156,236 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (21268 hom., cov: 32)
  • Exomes 𝑓: 0.42 (134968 hom.)
• Consequence: CYP1B1 NM_000104.4 missense
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: 0.334
• Publications: 546 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: Benign. The variant received -19 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.005228162).
• BP6: Variant 2-38071060-G-C is Benign according to our data. Variant chr2-38071060-G-C is described in ClinVar as Benign. ClinVar VariationId is 456637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.767 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.1294C>G	p.Leu432Val	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.1294C>G	p.Leu432Val	missense	Exon 3 of 3	ENSP00000478561.1	Q16678
	CYP1B1	ENST00000490576.2	TSL:4	c.1294C>G	p.Leu432Val	missense	Exon 3 of 3	ENSP00000478839.2	Q16678
	CYP1B1	ENST00000614273.1	TSL:5	c.1294C>G	p.Leu432Val	missense	Exon 3 of 3	ENSP00000483678.1	Q16678

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74816 AN: 151976 Hom.: 21223 Cov.: 32

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.446

GnomAD4 exome AF: 0.418 AC: 610248 AN: 1461292 Hom.: 134968 Cov.: 64 AF XY: 0.411 AC XY: 298608 AN XY: 726824

African (AFR) AF: 0.782 AC: 26157 AN: 33464

American (AMR) AF: 0.230 AC: 10265 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 12888 AN: 26132

East Asian (EAS) AF: 0.125 AC: 4973 AN: 39698

South Asian (SAS) AF: 0.220 AC: 18994 AN: 86248

European-Finnish (FIN) AF: 0.367 AC: 19579 AN: 53410

Middle Eastern (MID) AF: 0.344 AC: 1987 AN: 5768

European-Non Finnish (NFE) AF: 0.441 AC: 490604 AN: 1111504

Other (OTH) AF: 0.411 AC: 24801 AN: 60364

GnomAD4 genome AF: 0.493 AC: 74925 AN: 152094 Hom.: 21268 Cov.: 32 AF XY: 0.479 AC XY: 35574 AN XY: 74344

African (AFR) AF: 0.774 AC: 32106 AN: 41478

American (AMR) AF: 0.317 AC: 4852 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 1789 AN: 3468

East Asian (EAS) AF: 0.113 AC: 585 AN: 5184

South Asian (SAS) AF: 0.200 AC: 966 AN: 4820

European-Finnish (FIN) AF: 0.360 AC: 3801 AN: 10562

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.433 AC: 29445 AN: 67982

Other (OTH) AF: 0.443 AC: 936 AN: 2112

Alfa AF: 0.421 Hom.: 10147

Bravo AF: 0.503

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital glaucoma (1)
-	-	1	CYP1B1-related glaucoma with or without anterior segment dysgenesis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.9
DEOGEN2	Benign	0.077	T
LIST_S2	Benign	0.034	T
MetaRNN	Benign	0.0052	T
PhyloP100		0.33
Sift4G	Benign	0.29	T
Vest4		0.053
gMVP		0.69

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1056836; hg19: chr2-38298203;