rs12721655

Positions:

• chr19-41004377-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 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 (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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 no assertion criteria provided B:1
• Conservation: PhyloP100: 0.889

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 Benign. Variant got -9 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 id is 3033395.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 381 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2B6	NM_000767.5	c.415A>G	p.Lys139Glu	missense_variant	3/9	ENST00000324071.10	NP_000758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2B6	ENST00000324071.10	c.415A>G	p.Lys139Glu	missense_variant	3/9	1	NM_000767.5	ENSP00000324648	P1
CYP2B6	ENST00000593831.1	c.187A>G	p.Lys63Glu	missense_variant	2/5	2		ENSP00000470582
CYP2B6	ENST00000598834.2	c.319A>G	p.Lys107Glu	missense_variant, NMD_transcript_variant	3/10	5		ENSP00000496294
CYP2B6	ENST00000594187.1			upstream_gene_variant		5

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

GnomAD3 exomes AF: 0.00233 AC: 585 AN: 251312 Hom.: 1 AF XY: 0.00221 AC XY: 300 AN XY: 135832

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 SAS exome AF: 0.000654

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

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000557

Gnomad4 FIN exome AF: 0.000506

Gnomad4 NFE exome AF: 0.00496

Gnomad4 OTH exome AF: 0.00235

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

Gnomad4 AFR AF: 0.000892

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00454

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00365 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

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CYP2B6-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2022

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	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;T;T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.063
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.6	.;D;.
REVEL	Benign	0.29
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0010	.;D;D
Polyphen		0.99	D;D;.
Vest4		0.51, 0.65
MVP		0.78
MPC		0.42
ClinPred		0.043	T
GERP RS		3.8
Varity_R		0.92
gMVP		0.35

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

Other links and lift over

dbSNP: rs12721655; hg19: chr19-41510282;