19-41004133-G-T

Variant names:

• chr19-41004133-G-T
• rs148009906
• NM_000767.5:c.304G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000767.5(CYP2B6):​c.304G>T​(p.Ala102Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000459 in 1,543,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: CYP2B6 NM_000767.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.380
• Publications: 4 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.090845704).
• BS2: High AC in GnomAd4 at 18 AD gene.

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.304G>T	p.Ala102Ser	missense	Exon 2 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.304G>T	p.Ala102Ser	missense	Exon 2 of 9	ENSP00000324648.2	P20813-1
	CYP2B6	ENST00000593831.1	TSL:2	c.76G>T	p.Ala26Ser	missense	Exon 1 of 5	ENSP00000470582.1	M0QZJ2
	CYP2B6	ENST00000863358.1		c.172-2804G>T		intron	N/A	ENSP00000533417.1

Frequencies

GnomAD3 genomes AF: 0.000130 AC: 18 AN: 138874 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000258

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000915 AC: 23 AN: 251264 AF XY: 0.000103

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000492 AC: 691 AN: 1404986 Hom.: 0 Cov.: 34 AF XY: 0.000462 AC XY: 323 AN XY: 698688

African (AFR) AF: 0.0000314 AC: 1 AN: 31830

American (AMR) AF: 0.00 AC: 0 AN: 43100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24126

East Asian (EAS) AF: 0.0000292 AC: 1 AN: 34276

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85816

European-Finnish (FIN) AF: 0.0000208 AC: 1 AN: 47982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5508

European-Non Finnish (NFE) AF: 0.000628 AC: 676 AN: 1075676

Other (OTH) AF: 0.000194 AC: 11 AN: 56672

GnomAD4 genome AF: 0.000130 AC: 18 AN: 138874 Hom.: 0 Cov.: 29 AF XY: 0.000105 AC XY: 7 AN XY: 66632

African (AFR) AF: 0.0000267 AC: 1 AN: 37484

American (AMR) AF: 0.00 AC: 0 AN: 12458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3378

East Asian (EAS) AF: 0.00 AC: 0 AN: 4376

South Asian (SAS) AF: 0.00 AC: 0 AN: 4146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000258 AC: 17 AN: 65768

Other (OTH) AF: 0.00 AC: 0 AN: 1926

Alfa AF: 0.000160 Hom.: 0

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.38
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.12
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.023	D
Polyphen		0.38	B
Vest4		0.055
MVP		0.69
MPC		0.11
ClinPred		0.040	T
GERP RS		-0.97
PromoterAI		-0.097	Neutral
Varity_R		0.66
gMVP		0.30
Mutation Taster		=89/11	polymorphism

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: rs148009906; hg19: chr19-41510038;