rs12721655

Variant names:

• chr19-41004377-A-G
• rs12721655
• NM_000767.5:c.415A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000767.5(CYP2B6):​c.415A>G​(p.Lys139Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 1,614,004 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0040 (20 hom.)
• Consequence: CYP2B6 NM_000767.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.889
• Publications: 52 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010652304).
• BP6: Variant 19-41004377-A-G is Benign according to our data. Variant chr19-41004377-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3033395.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 381 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000767.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2B6	NM_000767.5	MANE Select	c.415A>G	p.Lys139Glu	missense	Exon 3 of 9	NP_000758.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2B6	ENST00000324071.10	TSL:1 MANE Select	c.415A>G	p.Lys139Glu	missense	Exon 3 of 9	ENSP00000324648.2
	CYP2B6	ENST00000593831.1	TSL:2	c.187A>G	p.Lys63Glu	missense	Exon 2 of 5	ENSP00000470582.1
	CYP2B6	ENST00000598834.2	TSL:5	n.316A>G		non_coding_transcript_exon	Exon 3 of 10	ENSP00000496294.1

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 381 AN: 152058 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000895

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00454

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00233 AC: 585 AN: 251312 AF XY: 0.00221

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00428

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00398 AC: 5816 AN: 1461828 Hom.: 20 Cov.: 33 AF XY: 0.00379 AC XY: 2757 AN XY: 727220

African (AFR) AF: 0.000597 AC: 20 AN: 33474

American (AMR) AF: 0.00125 AC: 56 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000557 AC: 48 AN: 86240

European-Finnish (FIN) AF: 0.000506 AC: 27 AN: 53400

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00496 AC: 5520 AN: 1111998

Other (OTH) AF: 0.00235 AC: 142 AN: 60396

GnomAD4 genome AF: 0.00250 AC: 381 AN: 152176 Hom.: 2 Cov.: 31 AF XY: 0.00207 AC XY: 154 AN XY: 74410

African (AFR) AF: 0.000892 AC: 37 AN: 41476

American (AMR) AF: 0.00150 AC: 23 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4814

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00454 AC: 309 AN: 68006

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00304 Hom.: 1

Bravo AF: 0.00249

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00228 AC: 277

EpiCase AF: 0.00338

EpiControl AF: 0.00350

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CYP2B6-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.063
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.89
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.51
MVP		0.78
MPC		0.42
ClinPred		0.043	T
GERP RS		3.8
PromoterAI		0.00080	Neutral
Varity_R		0.92
gMVP		0.35
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs12721655; hg19: chr19-41510282; COSMIC: COSV107363307;