19-41007013-T-C

Variant names:

• chr19-41007013-T-C
• rs36079186
• NM_000767.5:c.593T>C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000767.5(CYP2B6):​c.593T>C​(p.Met198Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000199 in 1,614,036 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (3 hom.)
• Consequence: CYP2B6 NM_000767.5 missense
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 5.76

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027706802).
• BS2: High AC in GnomAd4 at 93 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2B6	NM_000767.5	c.593T>C	p.Met198Thr	missense_variant	Exon 4 of 9	ENST00000324071.10	NP_000758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2B6	ENST00000324071.10	c.593T>C	p.Met198Thr	missense_variant	Exon 4 of 9	1	NM_000767.5	ENSP00000324648.2
CYP2B6	ENST00000593831.1	c.256+2567T>C		intron_variant	Intron 2 of 4	2		ENSP00000470582.1
CYP2B6	ENST00000594187.1	n.177T>C		non_coding_transcript_exon_variant	Exon 2 of 2	5
CYP2B6	ENST00000598834.2	n.494T>C		non_coding_transcript_exon_variant	Exon 4 of 10	5		ENSP00000496294.1

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152094 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000310 AC: 78 AN: 251454 Hom.: 1 AF XY: 0.000309 AC XY: 42 AN XY: 135900

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000157 AC: 229 AN: 1461824 Hom.: 3 Cov.: 33 AF XY: 0.000164 AC XY: 119 AN XY: 727212

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000893

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152212 Hom.: 0 Cov.: 31 AF XY: 0.000712 AC XY: 53 AN XY: 74418

Gnomad4 AFR AF: 0.00205

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000310 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000329 AC: 40

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Efavirenz response Other:1

Jan 01, 2006

Institute of Microbiology; University Hospital and Univeristy of Lausanne

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

- This variant was associated with very high efavirenz plasma levels in a HIV+individual

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Benign	0.78
DEOGEN2	Benign	0.042	T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.074	.;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.028	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.7	.;D
REVEL	Benign	0.18
Sift	Uncertain	0.0030	.;D
Sift4G	Pathogenic	0.0010	.;D
Polyphen		0.0	B;B
Vest4		0.13
MVP		0.30
MPC		0.074
ClinPred		0.045	T
GERP RS		4.4
Varity_R		0.49
gMVP		0.25

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

Other links and lift over

dbSNP: rs36079186; hg19: chr19-41512918;