rs2279343

Variant names:

• chr19-41009358-A-G
• rs2279343
• NM_000767.5:c.785A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-41009358-A-G
• chr19-41009358-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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 criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.784
• Publications: 383 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074420273).
• BP6: Variant 19-41009358-A-G is Benign according to our data. Variant chr19-41009358-A-G is described in ClinVar as Benign. ClinVar VariationId is 120171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2B6	NM_000767.5	c.785A>G	p.Lys262Arg	missense_variant	Exon 5 of 9	ENST00000324071.10	NP_000758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2B6	ENST00000324071.10	c.785A>G	p.Lys262Arg	missense_variant	Exon 5 of 9	1	NM_000767.5	ENSP00000324648.2
CYP2B6	ENST00000598834.2	n.*226A>G		non_coding_transcript_exon_variant	Exon 6 of 10	5		ENSP00000496294.1
CYP2B6	ENST00000598834.2	n.*226A>G		3_prime_UTR_variant	Exon 6 of 10	5		ENSP00000496294.1
CYP2B6	ENST00000593831.1	c.257-2940A>G		intron_variant	Intron 2 of 4	2		ENSP00000470582.1

Frequencies

GnomAD3 genomes AF: 0.293 AC: 42549 AN: 145088 Hom.: 6480 Cov.: 25

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

GnomAD2 exomes AF: 0.129 AC: 27016 AN: 208848 AF XY: 0.129

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.271 AC: 6839 AN: 25198

American (AMR) AF: 0.215 AC: 8136 AN: 37856

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 5470 AN: 21924

East Asian (EAS) AF: 0.226 AC: 8242 AN: 36392

South Asian (SAS) AF: 0.345 AC: 24676 AN: 71510

European-Finnish (FIN) AF: 0.192 AC: 9031 AN: 47084

Middle Eastern (MID) AF: 0.212 AC: 967 AN: 4564

European-Non Finnish (NFE) AF: 0.135 AC: 114515 AN: 849614

Other (OTH) AF: 0.197 AC: 9617 AN: 48770

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.356 AC: 13981 AN: 39228

American (AMR) AF: 0.338 AC: 4841 AN: 14334

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1076 AN: 3394

East Asian (EAS) AF: 0.271 AC: 1315 AN: 4856

South Asian (SAS) AF: 0.386 AC: 1693 AN: 4390

European-Finnish (FIN) AF: 0.224 AC: 2195 AN: 9802

Middle Eastern (MID) AF: 0.319 AC: 92 AN: 288

European-Non Finnish (NFE) AF: 0.252 AC: 16637 AN: 66030

Other (OTH) AF: 0.310 AC: 624 AN: 2010

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.276 Hom.: 2155

ExAC AF: 0.0920 AC: 11067

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Efavirenz response Benign:2 Other:1

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 15, 2015

OMIM

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 05, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

CYP2B6-related disorder Benign:1

Jul 22, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
LIST_S2	Benign	0.50	.;T
MetaRNN	Benign	0.0074	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-2.9	N;N
PhyloP100		0.78
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.9	.;N
REVEL	Benign	0.16
Sift	Benign	1.0	.;T
Sift4G	Benign	1.0	.;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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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