rs28399499

chr19-41012316-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Strong BA1

The NM_000767.5(CYP2B6):c.983T>C(p.Ile328Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00364 in 1,614,058 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.020 (111 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (85 hom.)
• Consequence: CYP2B6 NM_000767.5 missense
• Clinical Significance: drug response reviewed by expert panel B:1 O:1
• Conservation: PhyloP100: 7.60

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061822236).
• BP6: Variant 19-41012316-T-C is Benign according to our data. Variant chr19-41012316-T-C is described in ClinVar as [drug_response]. Clinvar id is 225985.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {drug_response=1, Benign=1}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2B6	NM_000767.5	c.983T>C	p.Ile328Thr	missense_variant	7/9	ENST00000324071.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2B6	ENST00000324071.10	c.983T>C	p.Ile328Thr	missense_variant	7/9	1	NM_000767.5	P1
CYP2B6	ENST00000597612.1	n.478T>C		non_coding_transcript_exon_variant	2/3	1
CYP2B6	ENST00000593831.1	c.275T>C	p.Ile92Thr	missense_variant	3/5	2
CYP2B6	ENST00000598834.2	c.*424T>C		3_prime_UTR_variant, NMD_transcript_variant	8/10	5

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3085 AN: 152082 Hom.: 110 Cov.: 32

Gnomad AFR AF: 0.0704

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00859

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00508 AC: 1277 AN: 251302 Hom.: 54 AF XY: 0.00355 AC XY: 482 AN XY: 135840

Gnomad AFR exome AF: 0.0694

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00191 AC: 2791 AN: 1461858 Hom.: 85 Cov.: 32 AF XY: 0.00165 AC XY: 1202 AN XY: 727236

Gnomad4 AFR exome AF: 0.0681

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000791

Gnomad4 OTH exome AF: 0.00391

GnomAD4 genome AF: 0.0203 AC: 3090 AN: 152200 Hom.: 111 Cov.: 32 AF XY: 0.0194 AC XY: 1447 AN XY: 74420

Gnomad4 AFR AF: 0.0703

Gnomad4 AMR AF: 0.00858

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00420 Hom.: 46

Bravo AF: 0.0229

ESP6500AA AF: 0.0622 AC: 274

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00646 AC: 784

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: drug response

Submissions summary: Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

CYP2B6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

nevirapine response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications. Drug-variant association: Toxicity

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.092	T;T;T
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0062	T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	3.9	H;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
Polyphen		0.99	D;D;.
Vest4		0.81, 0.86
MVP		0.92
MPC		0.45
ClinPred		0.084	T
GERP RS		4.3
Varity_R		0.92
gMVP		0.41

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: rs28399499; hg19: chr19-41518221; COSMIC: COSV57844857;