Genetic Variant CYP2B6:p.Ile391Asn (chr19-41012693-T-A) – 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.1172T>A(p.Ile391Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,614,074 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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 0.0048 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0078 ( 70 hom. )

Consequence

CYP2B6
NM_000767.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.65

Publications

39 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=0.016278386).

BS2

High AC in GnomAd4 at 728 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2B6	NM_000767.5 link	c.1172T>A	p.Ile391Asn	missense_variant	Exon 8 of 9	ENST00000324071.10	NP_000758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CYP2B6	ENST00000324071.10 link	c.1172T>A	p.Ile391Asn	missense_variant	Exon 8 of 9	1	NM_000767.5	ENSP00000324648.2
CYP2B6	ENST00000597612.1 link	n.647+208T>A		intron_variant	Intron 2 of 2	1
CYP2B6	ENST00000593831.1 link	c.464T>A	p.Ile155Asn	missense_variant	Exon 4 of 5	2		ENSP00000470582.1
CYP2B6	ENST00000598834.2 link	n.*593+208T>A		intron_variant	Intron 8 of 9	5		ENSP00000496294.1

Frequencies

GnomAD3 genomes

AF:

0.00478

AC:

728

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00842

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00437

AC:

1098

AN:

251386

AF XY:

0.00434

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.00814

Gnomad OTH exome

AF:

0.00505

GnomAD4 exome

AF:

0.00782

AC:

11428

AN:

1461812

Hom.:

Cov.:

AF XY:

0.00752

AC XY:

5468

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

33478

American (AMR)

AF:

0.00163

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00122

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000104

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00172

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00974

AC:

10834

AN:

1111990

Other (OTH)

AF:

0.00573

AC:

346

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

622

1244

1867

2489

3111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00478

AC:

728

AN:

152262

Hom.:

Cov.:

AF XY:

0.00443

AC XY:

330

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00214

AC:

AN:

41552

American (AMR)

AF:

0.00301

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00842

AC:

573

AN:

68014

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

101

135

169

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:

0.00616

Hom.:

Bravo

AF:

0.00480

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00826

AC:

ExAC

AF:

0.00458

AC:

556

EpiCase

AF:

0.00758

EpiControl

AF:

0.00741

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.045

T;T;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.74

.;T;T

M_CAP

Benign

0.0051

MetaRNN

Benign

0.016

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.085

N;N;.

PhyloP100

1.6

PrimateAI

Benign

0.38

PROVEAN

Pathogenic

-5.2

.;D;.

REVEL

Benign

0.11

Sift

Uncertain

0.0060

.;D;.

Sift4G

Uncertain

0.045

.;D;T

Polyphen

0.99

D;D;.

Vest4

0.47, 0.48

MVP

0.39

MPC

0.21

ClinPred

0.038

GERP RS

3.9

Varity_R

0.81

gMVP

0.32

Mutation Taster

=97/3

polymorphism

(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