Genetic Variant CYP2B6:p.Met46Val (chr19-40991441-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000767.5(CYP2B6):c.136A>G(p.Met46Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,613,972 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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 0.0022 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0034 ( 13 hom. )

Consequence

CYP2B6
NM_000767.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.661

Publications

44 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0121717155).

BS2

High AC in GnomAd4 at 340 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2B6	NM_000767.5 link	c.136A>G	p.Met46Val	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.136A>G	p.Met46Val	missense_variant	Exon 1 of 9	1	NM_000767.5	ENSP00000324648.2		P20813-1
CYP2B6	ENST00000598834.2 link	n.37A>G		non_coding_transcript_exon_variant	Exon 1 of 10	5		ENSP00000496294.1		A0A2R8YFA4

Frequencies

GnomAD3 genomes

AF:

0.00222

AC:

338

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000798

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00376

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00228

AC:

574

AN:

251416

AF XY:

0.00244

show subpopulations

Gnomad AFR exome

AF:

0.000862

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.00341

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00344

AC:

5027

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00347

AC XY:

2524

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00167

AC:

AN:

33474

American (AMR)

AF:

0.00179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000344

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.00232

AC:

200

AN:

86250

European-Finnish (FIN)

AF:

0.000599

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0117

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00395

AC:

4390

AN:

1112010

Other (OTH)

AF:

0.00316

AC:

191

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

269

538

806

1075

1344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

174

348

522

696

870

<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:

0.00223

AC:

340

AN:

152138

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

149

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.000820

AC:

AN:

41460

American (AMR)

AF:

0.00203

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00125

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00376

AC:

256

AN:

68014

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00309

Hom.:

Bravo

AF:

0.00230

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00227

AC:

275

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00420

EpiControl

AF:

0.00385

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.0028

T;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.77

.;T

M_CAP

Benign

0.0056

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.3

L;L

PhyloP100

0.66

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.2

.;N

REVEL

Benign

0.087

Sift

Benign

0.29

.;T

Sift4G

Benign

0.19

.;T

Polyphen

0.72

P;P

Vest4

0.20

MVP

0.14

MPC

0.077

ClinPred

0.021

GERP RS

0.64

PromoterAI

-0.11

Neutral

(source)

Varity_R

0.23

gMVP

0.62

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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