Genetic Variant CYP2B6:p.Arg487Cys (chr19-41016810-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000767.5(CYP2B6):c.1459C>T(p.Arg487Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,609,992 control chromosomes in the GnomAD database, including 10,479 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.083 ( 663 hom., cov: 31)

Exomes 𝑓: 0.11 ( 9816 hom. )

Consequence

CYP2B6
NM_000767.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.846

Variant links:

Genes affected

CYP2B6 (HGNC:2615): (cytochrome P450 family 2 subfamily B member 6) This gene, CYP2B6, 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. This protein localizes to the endoplasmic reticulum and its expression is induced by phenobarbital. The enzyme is known to metabolize some xenobiotics, such as the anti-cancer drugs cyclophosphamide and ifosphamide. Transcript variants for this gene have been described; however, it has not been resolved whether these transcripts are in fact produced by this gene or by a closely related pseudogene, CYP2B7. Both the gene and the pseudogene are located in the middle of a CYP2A pseudogene found in a large cluster of cytochrome P450 genes from the CYP2A, CYP2B and CYP2F subfamilies on chromosome 19q. [provided by RefSeq, Jul 2008]

CYP2B6 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019600987).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2B6	NM_000767.5 link	c.1459C>T	p.Arg487Cys	missense_variant	Exon 9 of 9	ENST00000324071.10	NP_000758.1	P20813-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2B6	ENST00000324071.10 link	c.1459C>T	p.Arg487Cys	missense_variant	Exon 9 of 9	1	NM_000767.5	ENSP00000324648.2		P20813-1

Frequencies

GnomAD3 genomes

AF:

0.0828

AC:

12588

AN:

152066

Hom.:

663

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0263

Gnomad AMI

AF:

0.177

Gnomad AMR

AF:

0.0540

Gnomad ASJ

AF:

0.110

Gnomad EAS

AF:

0.00501

Gnomad SAS

AF:

0.0729

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.0662

GnomAD3 exomes

AF:

0.0881

AC:

22063

AN:

250440

Hom.:

1147

AF XY:

0.0910

AC XY:

12316

AN XY:

135372

show subpopulations

Gnomad AFR exome

AF:

0.0258

Gnomad AMR exome

AF:

0.0442

Gnomad ASJ exome

AF:

0.105

Gnomad EAS exome

AF:

0.00169

Gnomad SAS exome

AF:

0.0803

Gnomad FIN exome

AF:

0.121

Gnomad NFE exome

AF:

0.118

Gnomad OTH exome

AF:

0.101

GnomAD4 exome

AF:

0.111

AC:

162029

AN:

1457808

Hom.:

9816

Cov.:

AF XY:

0.110

AC XY:

79645

AN XY:

725100

show subpopulations

Gnomad4 AFR exome

AF:

0.0244

Gnomad4 AMR exome

AF:

0.0454

Gnomad4 ASJ exome

AF:

0.103

Gnomad4 EAS exome

AF:

0.00794

Gnomad4 SAS exome

AF:

0.0775

Gnomad4 FIN exome

AF:

0.123

Gnomad4 NFE exome

AF:

0.123

Gnomad4 OTH exome

AF:

0.101

GnomAD4 genome

AF:

0.0827

AC:

12588

AN:

152184

Hom.:

663

Cov.:

AF XY:

0.0806

AC XY:

6000

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0263

Gnomad4 AMR

AF:

0.0539

Gnomad4 ASJ

AF:

0.110

Gnomad4 EAS

AF:

0.00502

Gnomad4 SAS

AF:

0.0732

Gnomad4 FIN

AF:

0.121

Gnomad4 NFE

AF:

0.122

Gnomad4 OTH

AF:

0.0655

Alfa

AF:

0.0921

Hom.:

267

Bravo

AF:

0.0759

TwinsUK

AF:

0.117

AC:

432

ALSPAC

AF:

0.116

AC:

447

ESP6500AA

AF:

0.0306

AC:

135

ESP6500EA

AF:

0.122

AC:

1047

ExAC

AF:

0.0894

AC:

10859

EpiCase

AF:

0.120

EpiControl

AF:

0.117

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.66

CADD

Benign

2.1

DANN

Benign

0.27

DEOGEN2

Benign

0.0065

T;T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0066

LIST_S2

Benign

0.22

.;T;T

MetaRNN

Benign

0.0020

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.91

N;N;.

PrimateAI

Benign

0.22

PROVEAN

Benign

1.9

.;N;.

REVEL

Benign

0.039

Sift

Benign

1.0

.;T;.

Sift4G

Benign

1.0

.;T;T

Polyphen

0.025

B;B;.

Vest4

0.033, 0.022

MPC

0.088

ClinPred

0.0031

GERP RS

-6.0

Varity_R

0.21

gMVP

0.62

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over