NM_000104.4:c.*1871C>T

Variant names:

• chr2-38068851-G-A
• rs9341266
• NM_000104.4:c.*1871C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000104.4(CYP1B1):​c.*1871C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0414 in 227,194 control chromosomes in the GnomAD database, including 269 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (176 hom., cov: 33)
  • Exomes 𝑓: 0.046 (93 hom.)
• Consequence: CYP1B1 NM_000104.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.60
• Publications: 17 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: ClinGen, Ambry Genetics
• glaucoma 3A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
• anterior segment dysgenesis 6

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-38068851-G-A is Benign according to our data. Variant chr2-38068851-G-A is described in ClinVar as [Benign]. Clinvar id is 335920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP1B1	NM_000104.4	c.*1871C>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000610745.5	NP_000095.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP1B1	ENST00000610745.5	c.*1871C>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_000104.4	ENSP00000478561.1
CYP1B1	ENST00000490576.2	c.*1871C>T		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000478839.2
CYP1B1	ENST00000714520.1	c.*1871C>T		3_prime_UTR_variant	Exon 3 of 3			ENSP00000519767.1
CYP1B1	ENST00000491456.1	n.184+327C>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0393 AC: 5978 AN: 152046 Hom.: 176 Cov.: 33

Gnomad AFR AF: 0.00886

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0399

Gnomad ASJ AF: 0.0608

Gnomad EAS AF: 0.0698

Gnomad SAS AF: 0.0927

Gnomad FIN AF: 0.0747

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0443

Gnomad OTH AF: 0.0431

GnomAD4 exome AF: 0.0458 AC: 3437 AN: 75030 Hom.: 93 Cov.: 0 AF XY: 0.0450 AC XY: 1562 AN XY: 34728

African (AFR) AF: 0.00855 AC: 31 AN: 3624

American (AMR) AF: 0.0273 AC: 63 AN: 2304

Ashkenazi Jewish (ASJ) AF: 0.0709 AC: 335 AN: 4724

East Asian (EAS) AF: 0.0404 AC: 430 AN: 10652

South Asian (SAS) AF: 0.0997 AC: 65 AN: 652

European-Finnish (FIN) AF: 0.0814 AC: 7 AN: 86

Middle Eastern (MID) AF: 0.0465 AC: 21 AN: 452

European-Non Finnish (NFE) AF: 0.0474 AC: 2195 AN: 46264

Other (OTH) AF: 0.0462 AC: 290 AN: 6272

GnomAD4 genome AF: 0.0392 AC: 5972 AN: 152164 Hom.: 176 Cov.: 33 AF XY: 0.0420 AC XY: 3127 AN XY: 74368

African (AFR) AF: 0.00884 AC: 367 AN: 41536

American (AMR) AF: 0.0399 AC: 610 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 211 AN: 3472

East Asian (EAS) AF: 0.0701 AC: 363 AN: 5176

South Asian (SAS) AF: 0.0925 AC: 446 AN: 4820

European-Finnish (FIN) AF: 0.0747 AC: 790 AN: 10574

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0443 AC: 3013 AN: 67976

Other (OTH) AF: 0.0436 AC: 92 AN: 2112

Alfa AF: 0.0427 Hom.: 426

Bravo AF: 0.0345

Asia WGS AF: 0.0690 AC: 239 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Irido-corneo-trabecular dysgenesis Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Glaucoma 3A Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.4
DANN	Benign	0.75
PhyloP100		1.6
Mutation Taster		=100/0	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: rs9341266; hg19: chr2-38295994;