2-38068407-T-TA

Variant names:

• chr2-38068407-T-TA
• rs561615550
• NM_000104.4:c.*2314dupT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000104.4(CYP1B1):​c.*2314dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00476 in 227,588 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0065 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: CYP1B1 NM_000104.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.186
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00646 (984/152316) while in subpopulation AFR AF = 0.0225 (936/41550). AF 95% confidence interval is 0.0213. There are 12 homozygotes in GnomAd4. There are 457 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP1B1	NM_000104.4	c.*2314dupT		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.*2314dupT		3_prime_UTR_variant	Exon 3 of 3	1	NM_000104.4	ENSP00000478561.1
CYP1B1	ENST00000490576.2	c.*2314dupT		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000478839.2
CYP1B1	ENST00000714520.1	c.*2314dupT		3_prime_UTR_variant	Exon 3 of 3			ENSP00000519767.1
CYP1B1	ENST00000491456.1	n.184+770dupT		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.00645 AC: 981 AN: 152198 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.00132 AC: 99 AN: 75272 Hom.: 0 Cov.: 0 AF XY: 0.000891 AC XY: 31 AN XY: 34780

African (AFR) AF: 0.0214 AC: 75 AN: 3502

American (AMR) AF: 0.00132 AC: 3 AN: 2280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4774

East Asian (EAS) AF: 0.00 AC: 0 AN: 10714

South Asian (SAS) AF: 0.00 AC: 0 AN: 638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 458

European-Non Finnish (NFE) AF: 0.000151 AC: 7 AN: 46266

Other (OTH) AF: 0.00221 AC: 14 AN: 6332

GnomAD4 genome AF: 0.00646 AC: 984 AN: 152316 Hom.: 12 Cov.: 33 AF XY: 0.00614 AC XY: 457 AN XY: 74488

African (AFR) AF: 0.0225 AC: 936 AN: 41550

American (AMR) AF: 0.00203 AC: 31 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68040

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00534 Hom.: 2

Bravo AF: 0.00740

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Irido-corneo-trabecular dysgenesis Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary congenital glaucoma Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs561615550; hg19: chr2-38295550;