2-38075247-G-C

Variant names:

• chr2-38075247-G-C
• rs10012
• NM_000104.4:c.142C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000104.4(CYP1B1):​c.142C>G​(p.Arg48Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 1,593,196 control chromosomes in the GnomAD database, including 74,187 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R48R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.36 (10687 hom., cov: 34)
  • Exomes 𝑓: 0.29 (63500 hom.)
• Consequence: CYP1B1 NM_000104.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.744
• Publications: 177 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-AS1 (HGNC:28543): (CYP1B1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 35 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Trascript score misZ: -2.0997 (below the threshold of 3.09). GenCC associations: The gene is linked to Peters anomaly, anterior segment dysgenesis 6, glaucoma 3A, CYP1B1-related glaucoma with or without anterior segment dysgenesis, congenital glaucoma.
• BP4: Computational evidence support a benign effect (MetaRNN=7.667002E-5).
• BP6: Variant 2-38075247-G-C is Benign according to our data. Variant chr2-38075247-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000104.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1B1	NM_000104.4	MANE Select	c.142C>G	p.Arg48Gly	missense	Exon 2 of 3	NP_000095.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1B1	ENST00000610745.5	TSL:1 MANE Select	c.142C>G	p.Arg48Gly	missense	Exon 2 of 3	ENSP00000478561.1
	CYP1B1	ENST00000490576.2	TSL:4	c.142C>G	p.Arg48Gly	missense	Exon 2 of 3	ENSP00000478839.2
	CYP1B1	ENST00000614273.1	TSL:5	c.142C>G	p.Arg48Gly	missense	Exon 2 of 3	ENSP00000483678.1

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54437 AN: 152054 Hom.: 10663 Cov.: 34

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.320

GnomAD2 exomes AF: 0.312 AC: 67344 AN: 215506 AF XY: 0.311

Gnomad AFR exome AF: 0.516

Gnomad AMR exome AF: 0.312

Gnomad ASJ exome AF: 0.225

Gnomad EAS exome AF: 0.190

Gnomad FIN exome AF: 0.359

Gnomad NFE exome AF: 0.289

Gnomad OTH exome AF: 0.297

GnomAD4 exome AF: 0.291 AC: 419924 AN: 1441022 Hom.: 63500 Cov.: 35 AF XY: 0.293 AC XY: 210007 AN XY: 715810

African (AFR) AF: 0.526 AC: 17549 AN: 33352

American (AMR) AF: 0.311 AC: 13165 AN: 42288

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 5852 AN: 25768

East Asian (EAS) AF: 0.148 AC: 5797 AN: 39198

South Asian (SAS) AF: 0.370 AC: 31229 AN: 84480

European-Finnish (FIN) AF: 0.357 AC: 16059 AN: 44926

Middle Eastern (MID) AF: 0.328 AC: 1648 AN: 5018

European-Non Finnish (NFE) AF: 0.281 AC: 310788 AN: 1106294

Other (OTH) AF: 0.299 AC: 17837 AN: 59698

GnomAD4 genome AF: 0.358 AC: 54510 AN: 152174 Hom.: 10687 Cov.: 34 AF XY: 0.362 AC XY: 26908 AN XY: 74398

African (AFR) AF: 0.516 AC: 21434 AN: 41526

American (AMR) AF: 0.322 AC: 4927 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 742 AN: 3470

East Asian (EAS) AF: 0.181 AC: 936 AN: 5160

South Asian (SAS) AF: 0.382 AC: 1842 AN: 4828

European-Finnish (FIN) AF: 0.367 AC: 3895 AN: 10610

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.287 AC: 19501 AN: 67970

Other (OTH) AF: 0.326 AC: 687 AN: 2110

Alfa AF: 0.242 Hom.: 869

Bravo AF: 0.356

TwinsUK AF: 0.258 AC: 957

ALSPAC AF: 0.278 AC: 1071

ESP6500AA AF: 0.506 AC: 2205

ESP6500EA AF: 0.270 AC: 2313

ExAC AF: 0.301 AC: 35804

Asia WGS AF: 0.315 AC: 1094 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 14, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Glaucoma 3A Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 rule this variant out of causing disease. Therefore, this variant is classified as benign.

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15958554, 11854439, 18573508, 10910054)

Anterior segment dysgenesis 6 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital glaucoma Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.7
DANN	Benign	0.40
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.000077	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.74
PrimateAI	Benign	0.46	T
Sift4G	Benign	0.29	T
Vest4		0.030
ClinPred		0.000019	T
GERP RS		-4.8
Varity_R		0.070
gMVP		0.48
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: rs10012; hg19: chr2-38302390; COSMIC: COSV53191035; COSMIC: COSV53191035;