chr19-41016810-C-G

Variant names:

• chr19-41016810-C-G
• rs3211371
• NM_000767.5:c.1459C>G
• CYP2B6 p.Arg487Gly

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_000767.5(CYP2B6):c.1459C>G (p.Arg487Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,390 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000009. 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.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CYP2B6 NM_000767.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.846
• Publications: 127 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: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000009 — very rare for AD/XL gene (threshold 0.0001) — PM2 moderate.
	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).

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>G p.Arg487Gly	missense	Exon 9 of 9	Prot: NP_000758.1 UniProt:

CYP2B6 NM_000767.5

MANE Select

HGVSc / HGVSpc.1459C>Gp.Arg487Gly

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>G p.Arg487Gly	missense	Exon 9 of 9	Prot: ENSP00000324648.2 UniProt:
	CYP2B6 ENST00000597612.1	TSL:1	n.812C>G	non_coding_transcript_exon	Exon 3 of 3	Prot:
	CYP2B6 ENST00000863358.1		c.1114C>G p.Arg372Gly	missense	Exon 7 of 7	Prot: ENSP00000533417.1 UniProt:

CYP2B6 ENST00000324071.10

TSL:1MANE Select

HGVSc / HGVSpc.1459C>Gp.Arg487Gly

Exon rankExon 9 of 9

missense

Prot: ENSP00000324648.2UniProt: P20813-1

CYP2B6 ENST00000597612.1

TSL:1

HGVSc / HGVSpn.812C>G

Exon rankExon 3 of 3

non_coding_transcript_exon

Prot:

CYP2B6 ENST00000863358.1

HGVSc / HGVSpc.1114C>Gp.Arg372Gly

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461390	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31
TOPMed (Bravo) Warning	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:285	AN:56180	Cov:

Showing 5 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	11
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.8
DANN	Benign	0.85
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.057	N
FuncVEP CTI	Pathogenic	0.42
GPN-Star LLR	N/A	-6.6
GPN-Star score	N/A	6.6
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.90	T
Mutation Taster	N/A	87/13	polymorphism
MutationAssessor	Benign	1.4	L
PhyloP100	Benign	-0.85
popEVE	Benign	-3.0
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.060
Sift	Benign	0.040	D
Sift4G	Benign	0.17	T
Varity_R	N/A	0.27
VESM-3B	Benign	-8.1

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar