chr19-41006936-G-T

Position:

chr19-41006936-G-T

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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 made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
CYP2B6	NM_000767.5 linkuse as main transcript	c.516G>T	p.Gln172His	missense_variant	4/9	ENST00000324071.10	NP_000758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2B6	ENST00000324071.10 linkuse as main transcript	c.516G>T	p.Gln172His	missense_variant	4/9	1	NM_000767.5	ENSP00000324648	P1	P20813-1
CYP2B6	ENST00000593831.1 linkuse as main transcript	c.256+2490G>T		intron_variant		2		ENSP00000470582
CYP2B6	ENST00000594187.1 linkuse as main transcript	n.100G>T		non_coding_transcript_exon_variant	2/2	5
CYP2B6	ENST00000598834.2 linkuse as main transcript	c.420G>T	p.Gln140His	missense_variant, NMD_transcript_variant	4/10	5		ENSP00000496294

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

GnomAD3 exomes

AF:

0.272

AC:

68292

AN:

251268

Hom.:

10029

AF XY:

0.276

AC XY:

37426

AN XY:

135780

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 SAS exome

AF:

0.389

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

Gnomad4 AFR exome

AF:

0.386

Gnomad4 AMR exome

AF:

0.318

Gnomad4 ASJ exome

AF:

0.268

Gnomad4 EAS exome

AF:

0.189

Gnomad4 SAS exome

AF:

0.387

Gnomad4 FIN exome

AF:

0.191

Gnomad4 NFE exome

AF:

0.241

Gnomad4 OTH exome

AF:

0.261

GnomAD4 genome

AF:

0.284

AC:

43174

AN:

151894

Hom.:

6654

Cov.:

AF XY:

0.284

AC XY:

21080

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.370

Gnomad4 AMR

AF:

0.341

Gnomad4 ASJ

AF:

0.263

Gnomad4 EAS

AF:

0.205

Gnomad4 SAS

AF:

0.377

Gnomad4 FIN

AF:

0.184

Gnomad4 NFE

AF:

0.237

Gnomad4 OTH

AF:

0.299

Alfa

AF:

0.258

Hom.:

5449

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2021

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

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

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

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

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

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

Efavirenz response

Other:1

drug response, no assertion criteria provided

literature only

OMIM

May 18, 2015

- -

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

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

MutationTaster

Benign

1.0

P;P

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over