NM_000767.5:c.1459C>T

Variant names:

• chr19-41016810-C-T
• rs3211371
• NM_000767.5:c.1459C>T
• CYP2B6 p.Arg487Cys

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-6 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -6 classification points (ACMG Germline Pathogenicity v2019). BS2BP4_Moderate

The NM_000767.5(CYP2B6):c.1459C>T (p.Arg487Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0827 (AC=12,588) in the gnomAD database across 152,184 control chromosomes, including 663 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.123. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.083 (663 hom., cov: 31)
  • Exomes 𝑓: 0.11 (9816 hom.)
• Consequence: CYP2B6 NM_000767.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.846
• Publications: 1 publications found

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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -6 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 663.; Very high cumulative gnomAD AC = 12588 (any gene).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000767.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CYP2B6 NM_000767.5	MANE Select	c.1459C>T p.Arg487Cys	missense	Exon 9 of 9	Prot: NP_000758.1 UniProt:

CYP2B6 NM_000767.5

MANE Select

HGVSc / HGVSpc.1459C>Tp.Arg487Cys

Exon rankExon 9 of 9

missense

Prot: NP_000758.1UniProt: P20813-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CYP2B6 ENST00000324071.10	TSL:1MANE Select	c.1459C>T p.Arg487Cys	missense	Exon 9 of 9	Prot: ENSP00000324648.2 UniProt:
	CYP2B6 ENST00000597612.1	TSL:1	n.812C>T	non_coding_transcript_exon	Exon 3 of 3	Prot:
	CYP2B6 ENST00000863358.1		c.1114C>T p.Arg372Cys	missense	Exon 7 of 7	Prot: ENSP00000533417.1 UniProt:

CYP2B6 ENST00000324071.10

TSL:1MANE Select

HGVSc / HGVSpc.1459C>Tp.Arg487Cys

Exon rankExon 9 of 9

missense

Prot: ENSP00000324648.2UniProt: P20813-1

CYP2B6 ENST00000597612.1

TSL:1

HGVSc / HGVSpn.812C>T

Exon rankExon 3 of 3

non_coding_transcript_exon

Prot:

CYP2B6 ENST00000863358.1

HGVSc / HGVSpc.1114C>Tp.Arg372Cys

Exon rankExon 7 of 7

missense

Prot: ENSP00000533417.1UniProt: A0ACI8QFV7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0828	AC:12588	Hom:663	AN:152066	Cov:31
GnomAD2 exomes	AF: 0.0881	AC:22063	Hom:	AN:250440	Cov:
GnomAD4 exome Warning	AF: 0.111	AC:162029	Hom:9816	AN:1457808	Cov:32
GnomAD4 genome	AF: 0.0827	AC:12588	Hom:663	AN:152184	Cov:31
TOPMed (Bravo)	AF: 0.0759	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0859	AC:4827	Hom:285	AN:56180	Cov:
Local & regional cohorts 8 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.00162	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0909	AC:1182	Hom:	AN:13006	Cov:
Korea4K (4,157 Koreans)	AF: 0.00207	AC:15	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.0434	AC:87	Hom:	AN:2004	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0140	AC:1711	Hom:12	AN:122156	Cov:
Turkish Variome	AF: 0.103	AC:160	Hom:8	AN:1546	Cov:
UK10K	AF: 0.116	AC:879	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.00179	AC:16	Hom:0	AN:8960	Cov:

Showing 14 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.121 *	1168	9614	0.124 *	1292	10418
BipEx(Bipolar disorder (including schizoaffective))	0.127	3608	28416	0.122	3520	28844
Epi25(Epilepsy)	0.102	4280	41952	0.103	6901	66866
SCHEMA(Schizophrenia)	0.0782	9178	117396	0.0912	18295	200712

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	8.5
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.1
DANN	Benign	0.27
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0066	N
FuncVEP CTI	Benign	0.094
GPN-Star LLR	N/A	-4.8
GPN-Star score	N/A	4.8
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	89/11	polymorphism (auto)
MutationAssessor	Benign	-0.91	N
PhyloP100	Benign	-0.85
popEVE	Benign	-2.0
PrimateAI	Benign	0.22	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.039
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Varity_R	N/A	0.21
VESM-3B	Benign	-5.1

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs3211371;

hg19: chr19-41522715;

COSMIC: COSV57843688;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar