Genetic Variant CYP2B6:p.Arg22Cys (chr19-40991369-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.64C>T(p.Arg22Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0479 in 1,613,998 control chromosomes in the GnomAD database, including 2,035 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.049 ( 220 hom., cov: 31)

Exomes 𝑓: 0.048 ( 1815 hom. )

Consequence

CYP2B6
NM_000767.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.168

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035538375).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2B6	NM_000767.5 link	c.64C>T	p.Arg22Cys	missense_variant	Exon 1 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.64C>T	p.Arg22Cys	missense_variant	Exon 1 of 9	1	NM_000767.5	ENSP00000324648.2		P20813-1
CYP2B6	ENST00000598834.2 link	n.-36C>T		upstream_gene_variant		5		ENSP00000496294.1		A0A2R8YFA4

Frequencies

GnomAD3 genomes

AF:

0.0489

AC:

7433

AN:

152050

Hom.:

220

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0364

Gnomad AMI

AF:

0.122

Gnomad AMR

AF:

0.0502

Gnomad ASJ

AF:

0.0880

Gnomad EAS

AF:

0.0491

Gnomad SAS

AF:

0.0338

Gnomad FIN

AF:

0.0493

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0535

Gnomad OTH

AF:

0.0636

GnomAD3 exomes

AF:

0.0479

AC:

12036

AN:

251420

Hom.:

326

AF XY:

0.0480

AC XY:

6516

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.0374

Gnomad AMR exome

AF:

0.0313

Gnomad ASJ exome

AF:

0.0799

Gnomad EAS exome

AF:

0.0450

Gnomad SAS exome

AF:

0.0311

Gnomad FIN exome

AF:

0.0488

Gnomad NFE exome

AF:

0.0561

Gnomad OTH exome

AF:

0.0543

GnomAD4 exome

AF:

0.0478

AC:

69839

AN:

1461830

Hom.:

1815

Cov.:

AF XY:

0.0478

AC XY:

34731

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0389

Gnomad4 AMR exome

AF:

0.0317

Gnomad4 ASJ exome

AF:

0.0818

Gnomad4 EAS exome

AF:

0.0497

Gnomad4 SAS exome

AF:

0.0305

Gnomad4 FIN exome

AF:

0.0488

Gnomad4 NFE exome

AF:

0.0485

Gnomad4 OTH exome

AF:

0.0536

GnomAD4 genome

AF:

0.0489

AC:

7438

AN:

152168

Hom.:

220

Cov.:

AF XY:

0.0492

AC XY:

3660

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0364

Gnomad4 AMR

AF:

0.0502

Gnomad4 ASJ

AF:

0.0880

Gnomad4 EAS

AF:

0.0494

Gnomad4 SAS

AF:

0.0336

Gnomad4 FIN

AF:

0.0493

Gnomad4 NFE

AF:

0.0535

Gnomad4 OTH

AF:

0.0629

Alfa

AF:

0.0511

Hom.:

128

Bravo

AF:

0.0472

TwinsUK

AF:

0.0458

AC:

170

ALSPAC

AF:

0.0431

AC:

166

ESP6500AA

AF:

0.0379

AC:

167

ESP6500EA

AF:

0.0536

AC:

461

ExAC

AF:

0.0490

AC:

5945

Asia WGS

AF:

0.0450

AC:

157

AN:

3478

EpiCase

AF:

0.0527

EpiControl

AF:

0.0574

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.036

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.58

.;T

MetaRNN

Benign

0.0036

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.4

.;N

REVEL

Benign

0.21

Sift

Uncertain

0.0010

.;D

Sift4G

Uncertain

0.0090

.;D

Polyphen

0.98

D;D

Vest4

0.083

MPC

0.19

ClinPred

0.035

GERP RS

-3.9

Varity_R

0.12

gMVP

0.46

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