19-41006936-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000767.5(CYP2B6):c.516G>T(p.Gln172His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,613,508 control chromosomes in the GnomAD database, including 55,845 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.28 ( 6654 hom., cov: 31)

Exomes 𝑓: 0.25 ( 49191 hom. )

Consequence

CYP2B6
NM_000767.5 missense

Scores

Clinical Significance

drug response reviewed by expert panel B:1O:4

Conservation

PhyloP100: -0.968

Publications

783 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020054579).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2B6	NM_000767.5 link	c.516G>T	p.Gln172His	missense_variant	Exon 4 of 9	ENST00000324071.10	NP_000758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CYP2B6	ENST00000324071.10 link	c.516G>T	p.Gln172His	missense_variant	Exon 4 of 9	1	NM_000767.5	ENSP00000324648.2
CYP2B6	ENST00000594187.1 link	n.100G>T		non_coding_transcript_exon_variant	Exon 2 of 2	5
CYP2B6	ENST00000598834.2 link	n.417G>T		non_coding_transcript_exon_variant	Exon 4 of 10	5		ENSP00000496294.1
CYP2B6	ENST00000593831.1 link	c.256+2490G>T		intron_variant	Intron 2 of 4	2		ENSP00000470582.1

Frequencies

GnomAD3 genomes

AF:

0.284

AC:

43158

AN:

151776

Hom.:

6654

Cov.:

show subpopulations

Gnomad AFR

AF:

0.371

Gnomad AMI

AF:

0.107

Gnomad AMR

AF:

0.341

Gnomad ASJ

AF:

0.263

Gnomad EAS

AF:

0.206

Gnomad SAS

AF:

0.379

Gnomad FIN

AF:

0.184

Gnomad MID

AF:

0.291

Gnomad NFE

AF:

0.237

Gnomad OTH

AF:

0.297

GnomAD2 exomes

AF:

0.272

AC:

68292

AN:

251268

AF XY:

0.276

show subpopulations

Gnomad AFR exome

AF:

0.372

Gnomad AMR exome

AF:

0.315

Gnomad ASJ exome

AF:

0.269

Gnomad EAS exome

AF:

0.191

Gnomad FIN exome

AF:

0.191

Gnomad NFE exome

AF:

0.242

Gnomad OTH exome

AF:

0.265

GnomAD4 exome

AF:

0.254

AC:

370589

AN:

1461614

Hom.:

49191

Cov.:

AF XY:

0.257

AC XY:

187203

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.386

AC:

12901

AN:

33464

American (AMR)

AF:

0.318

AC:

14238

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.268

AC:

7010

AN:

26136

East Asian (EAS)

AF:

0.189

AC:

7487

AN:

39698

South Asian (SAS)

AF:

0.387

AC:

33419

AN:

86252

European-Finnish (FIN)

AF:

0.191

AC:

10194

AN:

53404

Middle Eastern (MID)

AF:

0.277

AC:

1588

AN:

5730

European-Non Finnish (NFE)

AF:

0.241

AC:

267991

AN:

1111842

Other (OTH)

AF:

0.261

AC:

15761

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

14855

29710

44565

59420

74275

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9330

18660

27990

37320

46650

<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:

0.284

AC:

43174

AN:

151894

Hom.:

6654

Cov.:

AF XY:

0.284

AC XY:

21080

AN XY:

74236

show subpopulations

African (AFR)

AF:

0.370

AC:

15305

AN:

41338

American (AMR)

AF:

0.341

AC:

5202

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.263

AC:

914

AN:

3472

East Asian (EAS)

AF:

0.205

AC:

1059

AN:

5166

South Asian (SAS)

AF:

0.377

AC:

1811

AN:

4806

European-Finnish (FIN)

AF:

0.184

AC:

1948

AN:

10576

Middle Eastern (MID)

AF:

0.289

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.237

AC:

16120

AN:

67954

Other (OTH)

AF:

0.299

AC:

632

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1499

2998

4496

5995

7494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

428

856

1284

1712

2140

<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:

0.264

Hom.:

10216

Bravo

AF:

0.295

TwinsUK

AF:

0.248

AC:

919

ALSPAC

AF:

0.243

AC:

935

ESP6500AA

AF:

0.370

AC:

1629

ESP6500EA

AF:

0.250

AC:

2148

ExAC

AF:

0.273

AC:

33135

Asia WGS

AF:

0.317

AC:

1099

AN:

3478

EpiCase

AF:

0.249

EpiControl

AF:

0.251

ClinVar

Significance: drug response

Submissions summary: Benign:1Other:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

CYP2B6-related disorder

Benign:1

Jul 22, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

efavirenz response - Toxicity

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

nevirapine response - Metabolism/PK

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications. Drug-variant association: Metabolism/PK

efavirenz response - Metabolism/PK

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

Efavirenz response

Other:1

May 18, 2015

OMIM

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.0040

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.0039

T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.070

.;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.095

N;N

PhyloP100

-0.97

PrimateAI

Benign

0.32

PROVEAN

Benign

0.18

.;N

REVEL

Benign

0.066

Sift

Benign

0.16

.;T

Sift4G

Benign

0.22

.;T

Polyphen

0.0010

B;B

Vest4

0.0060

MutPred

0.18

Gain of catalytic residue at Q172 (P = 0.1486);Gain of catalytic residue at Q172 (P = 0.1486);

MPC

0.063

ClinPred

0.011

GERP RS

-9.0

Varity_R

0.27

gMVP

0.17

Mutation Taster

=93/7

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over