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rs28399499

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_StrongBA1

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

Scores

3
4
6

Clinical Significance

drug response reviewed by expert panel B:1O:1

Conservation

PhyloP100: 7.60
Variant links:
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]

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ACMG classification

Classification made for transcript

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: {Benign=1, drug_response=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
CYP2B6NM_000767.5 linkuse as main transcriptc.983T>C p.Ile328Thr missense_variant 7/9 ENST00000324071.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CYP2B6ENST00000324071.10 linkuse as main transcriptc.983T>C p.Ile328Thr missense_variant 7/91 NM_000767.5 P1P20813-1
CYP2B6ENST00000597612.1 linkuse as main transcriptn.478T>C non_coding_transcript_exon_variant 2/31
CYP2B6ENST00000593831.1 linkuse as main transcriptc.275T>C p.Ile92Thr missense_variant 3/52
CYP2B6ENST00000598834.2 linkuse as main transcriptc.*424T>C 3_prime_UTR_variant, NMD_transcript_variant 8/105

Frequencies

GnomAD3 genomes
AF:
0.0203
AC:
3085
AN:
152082
Hom.:
110
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:1Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

CYP2B6-related condition Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMay 02, 2019This 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 panelcurationPharmGKBMar 24, 2021PharmGKB 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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