chr2-38068407-T-TA

Position:

• chr2-38068407-T-TA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000104.4(CYP1B1):​c.*2314_*2315insT 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP1B1	NM_000104.4	c.*2314_*2315insT		3_prime_UTR_variant	3/3	ENST00000610745.5	NP_000095.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP1B1	ENST00000610745.5	c.*2314_*2315insT		3_prime_UTR_variant	3/3	1	NM_000104.4	ENSP00000478561	P1
CYP1B1	ENST00000490576.2	c.*2314_*2315insT		3_prime_UTR_variant	3/3	4		ENSP00000478839	P1
CYP1B1	ENST00000491456.1	n.184+770_184+771insT		intron_variant, non_coding_transcript_variant		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

Gnomad4 AFR exome AF: 0.0214

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000151

Gnomad4 OTH exome AF: 0.00221

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

Gnomad4 AFR AF: 0.0225

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00331

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Primary congenital glaucoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs561615550; hg19: chr2-38295550;