19-40991369-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000767.5(CYP2B6):c.64C>T(p.Arg22Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0479 in 1,613,998 control chromosomes in the GnomAD database, including 2,035 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.049 (220 hom., cov: 31)
  • Exomes 𝑓: 0.048 (1815 hom.)
• Consequence: CYP2B6 NM_000767.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.168

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035538375).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2B6	NM_000767.5	c.64C>T	p.Arg22Cys	missense_variant	1/9	ENST00000324071.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2B6	ENST00000324071.10	c.64C>T	p.Arg22Cys	missense_variant	1/9	1	NM_000767.5	P1
CYP2B6	ENST00000598834.2			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0489 AC: 7433 AN: 152050 Hom.: 220 Cov.: 31

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.0502

Gnomad ASJ AF: 0.0880

Gnomad EAS AF: 0.0491

Gnomad SAS AF: 0.0338

Gnomad FIN AF: 0.0493

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0535

Gnomad OTH AF: 0.0636

GnomAD3 exomes AF: 0.0479 AC: 12036 AN: 251420 Hom.: 326 AF XY: 0.0480 AC XY: 6516 AN XY: 135886

Gnomad AFR exome AF: 0.0374

Gnomad AMR exome AF: 0.0313

Gnomad ASJ exome AF: 0.0799

Gnomad EAS exome AF: 0.0450

Gnomad SAS exome AF: 0.0311

Gnomad FIN exome AF: 0.0488

Gnomad NFE exome AF: 0.0561

Gnomad OTH exome AF: 0.0543

GnomAD4 exome AF: 0.0478 AC: 69839 AN: 1461830 Hom.: 1815 Cov.: 32 AF XY: 0.0478 AC XY: 34731 AN XY: 727226

Gnomad4 AFR exome AF: 0.0389

Gnomad4 AMR exome AF: 0.0317

Gnomad4 ASJ exome AF: 0.0818

Gnomad4 EAS exome AF: 0.0497

Gnomad4 SAS exome AF: 0.0305

Gnomad4 FIN exome AF: 0.0488

Gnomad4 NFE exome AF: 0.0485

Gnomad4 OTH exome AF: 0.0536

GnomAD4 genome AF: 0.0489 AC: 7438 AN: 152168 Hom.: 220 Cov.: 31 AF XY: 0.0492 AC XY: 3660 AN XY: 74392

Gnomad4 AFR AF: 0.0364

Gnomad4 AMR AF: 0.0502

Gnomad4 ASJ AF: 0.0880

Gnomad4 EAS AF: 0.0494

Gnomad4 SAS AF: 0.0336

Gnomad4 FIN AF: 0.0493

Gnomad4 NFE AF: 0.0535

Gnomad4 OTH AF: 0.0629

Alfa AF: 0.0511 Hom.: 128

Bravo AF: 0.0472

TwinsUK AF: 0.0458 AC: 170

ALSPAC AF: 0.0431 AC: 166

ESP6500AA AF: 0.0379 AC: 167

ESP6500EA AF: 0.0536 AC: 461

ExAC AF: 0.0490 AC: 5945

Asia WGS AF: 0.0450 AC: 157 AN: 3478

EpiCase AF: 0.0527

EpiControl AF: 0.0574

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	13
Dann	Uncertain	0.98
DEOGEN2	Benign	0.036	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.010	N
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.42	T
Polyphen		0.98	D;D
Vest4		0.083
MPC		0.19
ClinPred		0.035	T
GERP RS		-3.9
Varity_R		0.12
gMVP		0.46

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: rs8192709; hg19: chr19-41497274; COSMIC: COSV60699104; COSMIC: COSV60699104;