2-38071026-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000104.4(CYP1B1):c.1328C>G(p.Ala443Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00331 in 1,614,070 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (47 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (39 hom.)
• Consequence: CYP1B1 NM_000104.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.05

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000104.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0049704313).
• BP6: Variant 2-38071026-G-C is Benign according to our data. Variant chr2-38071026-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 92435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0149 (2276/152252) while in subpopulation AFR AF= 0.0487 (2022/41532). AF 95% confidence interval is 0.0469. There are 47 homozygotes in gnomad4. There are 1089 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP1B1	NM_000104.4	c.1328C>G	p.Ala443Gly	missense_variant	3/3	ENST00000610745.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1B1	ENST00000610745.5	c.1328C>G	p.Ala443Gly	missense_variant	3/3	1	NM_000104.4	P1

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2265 AN: 152134 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.0485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00838

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00439 AC: 1105 AN: 251448 Hom.: 17 AF XY: 0.00333 AC XY: 453 AN XY: 135912

Gnomad AFR exome AF: 0.0474

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.00476

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.000932

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00210 AC: 3065 AN: 1461818 Hom.: 39 Cov.: 52 AF XY: 0.00193 AC XY: 1406 AN XY: 727208

Gnomad4 AFR exome AF: 0.0508

Gnomad4 AMR exome AF: 0.00450

Gnomad4 ASJ exome AF: 0.00348

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.000617

Gnomad4 OTH exome AF: 0.00475

GnomAD4 genome AF: 0.0149 AC: 2276 AN: 152252 Hom.: 47 Cov.: 33 AF XY: 0.0146 AC XY: 1089 AN XY: 74426

Gnomad4 AFR AF: 0.0487

Gnomad4 AMR AF: 0.00830

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.00178 Hom.: 2

Bravo AF: 0.0172

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0517 AC: 228

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00528 AC: 641

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00142

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 02, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Irido-corneo-trabecular dysgenesis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Glaucoma 3A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 10, 2020

This variant is associated with the following publications: (PMID: 16862072, 27884173, 11558822, 20981092, 23922489, 11854439, 19643970, 19793111, 15958554) -

Congenital glaucoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.23	N
MetaRNN	Benign	0.0050	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
Sift4G	Benign	0.29	T;T;T
Vest4		0.042
MVP		0.13
ClinPred		0.00063	T
GERP RS		4.2
Varity_R		0.11
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs4986888; hg19: chr2-38298169; COSMIC: COSV99029601; COSMIC: COSV99029601;