rs2279343

chr19-41009358-A-Gchr19-41009358-A-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000767.5(CYP2B6):c.785A>G(p.Lys262Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.29 (6478 hom., cov: 25)
  • Exomes 𝑓: 0.16 (38948 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP2B6 NM_000767.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.784

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074420273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2B6	NM_000767.5	c.785A>G	p.Lys262Arg	missense_variant	5/9	ENST00000324071.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2B6	ENST00000324071.10	c.785A>G	p.Lys262Arg	missense_variant	5/9	1	NM_000767.5	P1
CYP2B6	ENST00000593831.1	c.257-2940A>G		intron_variant		2
CYP2B6	ENST00000598834.2	c.*226A>G		3_prime_UTR_variant, NMD_transcript_variant	6/10	5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 42549 AN: 145088 Hom.: 6480 Cov.: 25 FAILED QC

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.308

GnomAD3 exomes AF: 0.129 AC: 27016 AN: 208848 Hom.: 7469 AF XY: 0.129 AC XY: 14529 AN XY: 112738

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.147

Gnomad SAS exome AF: 0.252

Gnomad FIN exome AF: 0.0752

Gnomad NFE exome AF: 0.0878

Gnomad OTH exome AF: 0.150

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.164 AC: 187493 AN: 1142912 Hom.: 38948 Cov.: 36 AF XY: 0.173 AC XY: 98990 AN XY: 573654

Gnomad4 AFR exome AF: 0.271

Gnomad4 AMR exome AF: 0.215

Gnomad4 ASJ exome AF: 0.249

Gnomad4 EAS exome AF: 0.226

Gnomad4 SAS exome AF: 0.345

Gnomad4 FIN exome AF: 0.192

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.197

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.293 AC: 42562 AN: 145210 Hom.: 6478 Cov.: 25 AF XY: 0.293 AC XY: 20728 AN XY: 70634

Gnomad4 AFR AF: 0.356

Gnomad4 AMR AF: 0.338

Gnomad4 ASJ AF: 0.317

Gnomad4 EAS AF: 0.271

Gnomad4 SAS AF: 0.386

Gnomad4 FIN AF: 0.224

Gnomad4 NFE AF: 0.252

Gnomad4 OTH AF: 0.310

Alfa AF: 0.251 Hom.: 1054

ExAC AF: 0.0920 AC: 11067

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Efavirenz response Benign:2 Other:1

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
drug response, no assertion criteria provided	literature only	OMIM	May 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Aug 05, 2015	- -

CYP2B6-related disorder Benign:1

Likely benign, criteria provided, single submitter

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.081
DANN	Benign	0.13
DEOGEN2	Benign	0.0015	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.012	N
MetaRNN	Benign	0.0074	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-2.9	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.24	T
Polyphen		0.0	B;B
Vest4		0.021
MPC		0.057
ClinPred		0.0052	T
GERP RS		-1.7
Varity_R		0.055
gMVP		0.096

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs2279343; hg19: chr19-41515263; COSMIC: COSV57842539; COSMIC: COSV57842539;