rs35303484

Positions:

• chr19-40991441-A-G
• chr19-40991441-A-T

Variant summary

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

The NM_000767.5(CYP2B6):​c.136A>G​(p.Met46Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,613,972 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0034 (13 hom.)
• Consequence: CYP2B6 NM_000767.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.661

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=0.0121717155).
• BS2: High AC in GnomAd4 at 340 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2B6	NM_000767.5	c.136A>G	p.Met46Val	missense_variant	1/9	ENST00000324071.10	NP_000758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2B6	ENST00000324071.10	c.136A>G	p.Met46Val	missense_variant	1/9	1	NM_000767.5	ENSP00000324648	P1
CYP2B6	ENST00000598834.2	c.40A>G	p.Met14Val	missense_variant, NMD_transcript_variant	1/10	5		ENSP00000496294

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 338 AN: 152020 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000798

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00376

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00228 AC: 574 AN: 251416 Hom.: 5 AF XY: 0.00244 AC XY: 332 AN XY: 135884

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00229

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00341

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00344 AC: 5027 AN: 1461834 Hom.: 13 Cov.: 32 AF XY: 0.00347 AC XY: 2524 AN XY: 727214

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00232

Gnomad4 FIN exome AF: 0.000599

Gnomad4 NFE exome AF: 0.00395

Gnomad4 OTH exome AF: 0.00316

GnomAD4 genome AF: 0.00223 AC: 340 AN: 152138 Hom.: 2 Cov.: 31 AF XY: 0.00200 AC XY: 149 AN XY: 74358

Gnomad4 AFR AF: 0.000820

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00376

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00341 Hom.: 2

Bravo AF: 0.00230

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00227 AC: 275

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00385

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.41
DEOGEN2	Benign	0.0028	T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.77	.;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.2	.;N
REVEL	Benign	0.087
Sift	Benign	0.29	.;T
Sift4G	Benign	0.19	.;T
Polyphen		0.72	P;P
Vest4		0.20
MVP		0.14
MPC		0.077
ClinPred		0.021	T
GERP RS		0.64
Varity_R		0.23
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35303484; hg19: chr19-41497346;