Genetic Variant CYP2B6:p.Arg22Cys (chr19-40991369-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

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

Publications

121 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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

GnomAD2 exomes

AF:

0.0479

AC:

12036

AN:

251420

AF XY:

0.0480

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 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

African (AFR)

AF:

0.0389

AC:

1301

AN:

33472

American (AMR)

AF:

0.0317

AC:

1416

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0818

AC:

2139

AN:

26134

East Asian (EAS)

AF:

0.0497

AC:

1972

AN:

39698

South Asian (SAS)

AF:

0.0305

AC:

2628

AN:

86254

European-Finnish (FIN)

AF:

0.0488

AC:

2609

AN:

53414

Middle Eastern (MID)

AF:

0.100

AC:

577

AN:

5766

European-Non Finnish (NFE)

AF:

0.0485

AC:

53960

AN:

1111972

Other (OTH)

AF:

0.0536

AC:

3237

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

4060

8119

12179

16238

20298

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1962

3924

5886

7848

9810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0489

AC:

7438

AN:

152168

Hom.:

220

Cov.:

AF XY:

0.0492

AC XY:

3660

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0364

AC:

1510

AN:

41480

American (AMR)

AF:

0.0502

AC:

767

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0880

AC:

305

AN:

3466

East Asian (EAS)

AF:

0.0494

AC:

256

AN:

5180

South Asian (SAS)

AF:

0.0336

AC:

162

AN:

4818

European-Finnish (FIN)

AF:

0.0493

AC:

523

AN:

10608

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0535

AC:

3639

AN:

68004

Other (OTH)

AF:

0.0629

AC:

133

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

355

709

1064

1418

1773

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0476

Hom.:

166

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

(source)

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

PhyloP100

-0.17

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

PromoterAI

-0.061

Neutral

(source)

Varity_R

0.12

gMVP

0.46

Mutation Taster

=89/11

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over