19-41016810-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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 frequency of 0.108 in 1,609,992 control chromosomes in the GnomAD database, including 10,479 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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: 213 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019600987).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000767.5. You can select a different transcript below to see updated ACMG 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	NP_000758.1	P20813-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2B6	ENST00000324071.10	TSL:1 MANE Select	c.1459C>T	p.Arg487Cys	missense	Exon 9 of 9	ENSP00000324648.2	P20813-1
	CYP2B6	ENST00000597612.1	TSL:1	n.812C>T		non_coding_transcript_exon	Exon 3 of 3
	CYP2B6	ENST00000863358.1		c.1114C>T	p.Arg372Cys	missense	Exon 7 of 7	ENSP00000533417.1

Frequencies

GnomAD3 genomes AF: 0.0828 AC: 12588 AN: 152066 Hom.: 663 Cov.: 31

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.0540

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.0729

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.0662

GnomAD2 exomes AF: 0.0881 AC: 22063 AN: 250440 AF XY: 0.0910

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.0442

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.00169

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.111 AC: 162029 AN: 1457808 Hom.: 9816 Cov.: 32 AF XY: 0.110 AC XY: 79645 AN XY: 725100

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0244 AC: 815 AN: 33458

American (AMR) AF: 0.0454 AC: 2028 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2694 AN: 26080

East Asian (EAS) AF: 0.00794 AC: 315 AN: 39692

South Asian (SAS) AF: 0.0775 AC: 6676 AN: 86156

European-Finnish (FIN) AF: 0.123 AC: 6579 AN: 53352

Middle Eastern (MID) AF: 0.0689 AC: 397 AN: 5758

European-Non Finnish (NFE) AF: 0.123 AC: 136417 AN: 1108390

Other (OTH) AF: 0.101 AC: 6108 AN: 60248

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0827 AC: 12588 AN: 152184 Hom.: 663 Cov.: 31 AF XY: 0.0806 AC XY: 6000 AN XY: 74408

African (AFR) AF: 0.0263 AC: 1091 AN: 41530

American (AMR) AF: 0.0539 AC: 825 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 383 AN: 3470

East Asian (EAS) AF: 0.00502 AC: 26 AN: 5180

South Asian (SAS) AF: 0.0732 AC: 353 AN: 4822

European-Finnish (FIN) AF: 0.121 AC: 1284 AN: 10594

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8307 AN: 67982

Other (OTH) AF: 0.0655 AC: 138 AN: 2108

Alfa AF: 0.0921 Hom.: 267

Bravo AF: 0.0759

TwinsUK AF: 0.117 AC: 432

ALSPAC AF: 0.116 AC: 447

ESP6500AA AF: 0.0306 AC: 135

ESP6500EA AF: 0.122 AC: 1047

ExAC AF: 0.0894 AC: 10859

EpiCase AF: 0.120

EpiControl AF: 0.117

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
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
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.91	N
PhyloP100		-0.85
PrimateAI	Benign	0.22	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.039
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.025	B
Vest4		0.033
MPC		0.088
ClinPred		0.0031	T
GERP RS		-6.0
Varity_R		0.21
gMVP		0.62
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3211371; hg19: chr19-41522715; COSMIC: COSV57843688;