rs34826503

Variant names:

• chr19-41012339-C-T
• rs34826503
• NM_000767.5:c.1006C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000767.5(CYP2B6):​c.1006C>T​(p.Arg336Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R336H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: CYP2B6 NM_000767.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.986
• Publications: 18 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022292167).
• BS2: High AC in GnomAd4 at 122 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2B6	NM_000767.5	c.1006C>T	p.Arg336Cys	missense_variant	Exon 7 of 9	ENST00000324071.10	NP_000758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2B6	ENST00000324071.10	c.1006C>T	p.Arg336Cys	missense_variant	Exon 7 of 9	1	NM_000767.5	ENSP00000324648.2

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152134 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000215 AC: 54 AN: 251324 AF XY: 0.000155

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000992 AC: 145 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.0000839 AC XY: 61 AN XY: 727228

African (AFR) AF: 0.00272 AC: 91 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000630 AC: 25 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111998

Other (OTH) AF: 0.000132 AC: 8 AN: 60394

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152252 Hom.: 0 Cov.: 31 AF XY: 0.000806 AC XY: 60 AN XY: 74440

African (AFR) AF: 0.00262 AC: 109 AN: 41544

American (AMR) AF: 0.000458 AC: 7 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000317 Hom.: 0

Bravo AF: 0.000861

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000305 AC: 37

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T;T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.86	.;D;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.022	T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Pathogenic	3.1	M;M;.
PhyloP100		0.99
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-7.2	.;D;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0060	.;D;.
Sift4G	Uncertain	0.0050	.;D;D
Polyphen		0.35	B;B;.
Vest4		0.41, 0.41
MVP		0.81
MPC		0.15
ClinPred		0.18	T
GERP RS		2.1
Varity_R		0.78
gMVP		0.42
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs34826503; hg19: chr19-41518244; COSMIC: COSV106431972;