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rs1800440

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000104.4(CYP1B1):c.1358A>G(p.Asn453Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,614,006 control chromosomes in the GnomAD database, including 25,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1623 hom., cov: 32)
Exomes 𝑓: 0.18 ( 24213 hom. )

Consequence

CYP1B1
NM_000104.4 missense

Scores

7
7

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 7.91
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0016258061).
BP6
Variant 2-38070996-T-C is Benign according to our data. Variant chr2-38070996-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 166969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-38070996-T-C is described in Lovd as [Benign]. Variant chr2-38070996-T-C is described in Lovd as [Pathogenic].
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CYP1B1NM_000104.4 linkuse as main transcriptc.1358A>G p.Asn453Ser missense_variant 3/3 ENST00000610745.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CYP1B1ENST00000610745.5 linkuse as main transcriptc.1358A>G p.Asn453Ser missense_variant 3/31 NM_000104.4 P1

Frequencies

GnomAD3 genomes
AF:
0.130
AC:
19711
AN:
152108
Hom.:
1626
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0350
Gnomad AMI
AF:
0.0899
Gnomad AMR
AF:
0.134
Gnomad ASJ
AF:
0.163
Gnomad EAS
AF:
0.00462
Gnomad SAS
AF:
0.216
Gnomad FIN
AF:
0.148
Gnomad MID
AF:
0.180
Gnomad NFE
AF:
0.184
Gnomad OTH
AF:
0.158
GnomAD3 exomes
AF:
0.153
AC:
38541
AN:
251460
Hom.:
3557
AF XY:
0.164
AC XY:
22275
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.0311
Gnomad AMR exome
AF:
0.114
Gnomad ASJ exome
AF:
0.166
Gnomad EAS exome
AF:
0.00337
Gnomad SAS exome
AF:
0.228
Gnomad FIN exome
AF:
0.146
Gnomad NFE exome
AF:
0.186
Gnomad OTH exome
AF:
0.173
GnomAD4 exome
AF:
0.175
AC:
256523
AN:
1461780
Hom.:
24213
Cov.:
33
AF XY:
0.178
AC XY:
129501
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.0274
Gnomad4 AMR exome
AF:
0.116
Gnomad4 ASJ exome
AF:
0.163
Gnomad4 EAS exome
AF:
0.00267
Gnomad4 SAS exome
AF:
0.229
Gnomad4 FIN exome
AF:
0.146
Gnomad4 NFE exome
AF:
0.186
Gnomad4 OTH exome
AF:
0.168
GnomAD4 genome
AF:
0.129
AC:
19705
AN:
152226
Hom.:
1623
Cov.:
32
AF XY:
0.129
AC XY:
9579
AN XY:
74432
show subpopulations
Gnomad4 AFR
AF:
0.0349
Gnomad4 AMR
AF:
0.134
Gnomad4 ASJ
AF:
0.163
Gnomad4 EAS
AF:
0.00463
Gnomad4 SAS
AF:
0.216
Gnomad4 FIN
AF:
0.148
Gnomad4 NFE
AF:
0.185
Gnomad4 OTH
AF:
0.155
Alfa
AF:
0.171
Hom.:
5814
Bravo
AF:
0.124
TwinsUK
AF:
0.191
AC:
710
ALSPAC
AF:
0.177
AC:
682
ESP6500AA
AF:
0.0334
AC:
147
ESP6500EA
AF:
0.187
AC:
1608
ExAC
AF:
0.155
AC:
18793
Asia WGS
AF:
0.0880
AC:
307
AN:
3478
EpiCase
AF:
0.191
EpiControl
AF:
0.196

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 03, 2014- -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 03, 2021- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Glaucoma 3A Benign:2
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 30, 2021- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015This variant is associated with the following publications: (PMID: 15958554, 11854439, 15486049, 23861929, 10426814, 24604202) -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2016- -
Anterior segment dysgenesis 6 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 30, 2021- -
Glaucoma 3, primary infantile, B;C1856439:Glaucoma 3A;C4310623:Anterior segment dysgenesis 6 Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 12, 2022- -
Congenital glaucoma Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.63
T
BayesDel_noAF
Benign
-0.53
Cadd
Uncertain
24
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.47
T;T;T
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.92
D
MetaRNN
Benign
0.0016
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.0
M;.;M
MutationTaster
Benign
0.000091
P;P
PrimateAI
Benign
0.29
T
Sift4G
Uncertain
0.0080
D;T;D
Vest4
0.089
ClinPred
0.012
T
GERP RS
6.0
Varity_R
0.30
gMVP
0.82

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1800440; hg19: chr2-38298139; COSMIC: COSV52221635; COSMIC: COSV52221635; API