rs45482602

chr19-41009350-C-Achr19-41009350-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000767.5(CYP2B6):c.777C>A(p.Ser259Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,580,936 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts 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. Synonymous variant affecting the same amino acid position (i.e. S259S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 27)
  • Exomes 𝑓: 0.0019 (37 hom.)
• Consequence: CYP2B6 NM_000767.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.55

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068685114).
• BP6: Variant 19-41009350-C-A is Benign according to our data. Variant chr19-41009350-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2649919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41009350-C-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 228 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2B6	NM_000767.5	c.777C>A	p.Ser259Arg	missense_variant	5/9	ENST00000324071.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2B6	ENST00000324071.10	c.777C>A	p.Ser259Arg	missense_variant	5/9	1	NM_000767.5	P1
CYP2B6	ENST00000593831.1	c.257-2948C>A		intron_variant		2
CYP2B6	ENST00000598834.2	c.*218C>A		3_prime_UTR_variant, NMD_transcript_variant	6/10	5

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 228 AN: 150652 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.000270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00213

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00171

Gnomad FIN AF: 0.000383

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.00145

GnomAD3 exomes AF: 0.00248 AC: 609 AN: 245372 Hom.: 6 AF XY: 0.00266 AC XY: 353 AN XY: 132578

Gnomad AFR exome AF: 0.000459

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.0160

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00240

Gnomad FIN exome AF: 0.000372

Gnomad NFE exome AF: 0.00252

Gnomad OTH exome AF: 0.00398

GnomAD4 exome AF: 0.00190 AC: 2713 AN: 1430166 Hom.: 37 Cov.: 33 AF XY: 0.00197 AC XY: 1403 AN XY: 712156

Gnomad4 AFR exome AF: 0.000561

Gnomad4 AMR exome AF: 0.00173

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00218

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00161

Gnomad4 OTH exome AF: 0.00294

GnomAD4 genome AF: 0.00151 AC: 228 AN: 150770 Hom.: 1 Cov.: 27 AF XY: 0.00160 AC XY: 118 AN XY: 73588

Gnomad4 AFR AF: 0.000269

Gnomad4 AMR AF: 0.00212

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00171

Gnomad4 FIN AF: 0.000383

Gnomad4 NFE AF: 0.00181

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.00248 Hom.: 0

Bravo AF: 0.00181

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00292 AC: 25

ExAC AF: 0.00248 AC: 300

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

CYP2B6: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	2.5
Dann	Uncertain	0.99
DEOGEN2	Benign	0.014	T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.055	N
MetaRNN	Benign	0.0069	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
Polyphen		1.0	D;D
Vest4		0.10
MutPred		0.16		Gain of solvent accessibility (P = 0.0155);Gain of solvent accessibility (P = 0.0155);
MVP		0.30
MPC		0.23
ClinPred		0.049	T
GERP RS		-3.3
Varity_R		0.70
gMVP		0.093

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: rs45482602; hg19: chr19-41515255;