Genetic Variant NM_000767.5:c.547G>A (chr19-41006967-G-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.547G>A(p.Val183Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00477 in 1,613,900 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V183G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0035 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0049 ( 33 hom. )

Consequence

CYP2B6
NM_000767.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.82

Publications

14 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016809613).

BS2

High AC in GnomAd4 at 526 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2B6	NM_000767.5 link	c.547G>A	p.Val183Ile	missense_variant	Exon 4 of 9	ENST00000324071.10	NP_000758.1	P20813-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYP2B6	ENST00000324071.10 link	c.547G>A	p.Val183Ile	missense_variant	Exon 4 of 9	1	NM_000767.5	ENSP00000324648.2	P20813-1
CYP2B6	ENST00000594187.1 link	n.131G>A		non_coding_transcript_exon_variant	Exon 2 of 2	5
CYP2B6	ENST00000598834.2 link	n.448G>A		non_coding_transcript_exon_variant	Exon 4 of 10	5		ENSP00000496294.1	A0A2R8YFA4
CYP2B6	ENST00000593831.1 link	c.256+2521G>A		intron_variant	Intron 2 of 4	2		ENSP00000470582.1	M0QZJ2

Frequencies

GnomAD3 genomes

AF:

0.00347

AC:

527

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00237

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00243

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00519

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00326

AC:

820

AN:

251438

AF XY:

0.00307

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.00231

Gnomad ASJ exome

AF:

0.00338

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00516

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00490

AC:

7167

AN:

1461812

Hom.:

Cov.:

AF XY:

0.00479

AC XY:

3486

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

33472

American (AMR)

AF:

0.00253

AC:

113

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00310

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00109

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00144

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00585

AC:

6502

AN:

1111948

Other (OTH)

AF:

0.00383

AC:

231

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

336

671

1007

1342

1678

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

256

512

768

1024

1280

<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:

0.00346

AC:

526

AN:

152088

Hom.:

Cov.:

AF XY:

0.00339

AC XY:

252

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.00237

AC:

AN:

41430

American (AMR)

AF:

0.00242

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00518

AC:

352

AN:

68016

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00405

Hom.:

Bravo

AF:

0.00345

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00325

AC:

394

EpiCase

AF:

0.00436

EpiControl

AF:

0.00539

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.0053

T;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.62

.;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.8

L;L

PhyloP100

3.8

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.75

.;N

REVEL

Benign

0.23

Sift

Benign

0.39

.;T

Sift4G

Benign

0.39

.;T

Polyphen

0.0020

B;B

Vest4

0.34

MVP

0.60

MPC

0.069

ClinPred

0.0094

GERP RS

4.5

Varity_R

0.23

gMVP

0.061

Mutation Taster

=33/67

disease causing

(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