2-38068564-A-G

Variant names:

• chr2-38068564-A-G
• rs112948057
• NM_000104.4:c.*2158T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000104.4(CYP1B1):​c.*2158T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0077 in 227,614 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (43 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (2 hom.)
• Consequence: CYP1B1 NM_000104.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.0210
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-38068564-A-G is Benign according to our data. Variant chr2-38068564-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 335916.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0103 (1575/152342) while in subpopulation AFR AF = 0.0364 (1513/41570). AF 95% confidence interval is 0.0349. There are 43 homozygotes in GnomAd4. There are 711 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP1B1	NM_000104.4	c.*2158T>C		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.*2158T>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_000104.4	ENSP00000478561.1
CYP1B1	ENST00000490576.2	c.*2158T>C		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000478839.2
CYP1B1	ENST00000714520.1	c.*2158T>C		3_prime_UTR_variant	Exon 3 of 3			ENSP00000519767.1
CYP1B1	ENST00000491456.1	n.184+614T>C		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1568 AN: 152224 Hom.: 43 Cov.: 33

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00235 AC: 177 AN: 75272 Hom.: 2 Cov.: 0 AF XY: 0.00209 AC XY: 73 AN XY: 34918

African (AFR) AF: 0.0390 AC: 138 AN: 3542

American (AMR) AF: 0.00265 AC: 6 AN: 2260

Ashkenazi Jewish (ASJ) AF: 0.000629 AC: 3 AN: 4766

East Asian (EAS) AF: 0.0000934 AC: 1 AN: 10708

South Asian (SAS) AF: 0.00 AC: 0 AN: 650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 444

European-Non Finnish (NFE) AF: 0.000173 AC: 8 AN: 46174

Other (OTH) AF: 0.00336 AC: 21 AN: 6250

GnomAD4 genome AF: 0.0103 AC: 1575 AN: 152342 Hom.: 43 Cov.: 33 AF XY: 0.00954 AC XY: 711 AN XY: 74498

African (AFR) AF: 0.0364 AC: 1513 AN: 41570

American (AMR) AF: 0.00294 AC: 45 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00557 Hom.: 19

Bravo AF: 0.0123

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Glaucoma 3A Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Irido-corneo-trabecular dysgenesis Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.0
DANN	Benign	0.61
PhyloP100		-0.021
Mutation Taster		=100/0	polymorphism

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: rs112948057; hg19: chr2-38295707;