chr19-41004133-G-A

Variant names:

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

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>A​(p.Ala102Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000194 in 1,543,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A102S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000022 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: CYP2B6 NM_000767.5 missense
• Clinical Significance: Not reported in ClinVar
• 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=0.25404254).
• BS2: High AC in GnomAdExome4 at 27 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>A	p.Ala102Thr	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>A	p.Ala102Thr	missense	Exon 2 of 9	ENSP00000324648.2	P20813-1
	CYP2B6	ENST00000593831.1	TSL:2	c.76G>A	p.Ala26Thr	missense	Exon 1 of 5	ENSP00000470582.1	M0QZJ2
	CYP2B6	ENST00000863358.1		c.172-2804G>A		intron	N/A	ENSP00000533417.1

Frequencies

GnomAD3 genomes AF: 0.0000216 AC: 3 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: 0.0000304

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251264 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000192 AC: 27 AN: 1404986 Hom.: 0 Cov.: 34 AF XY: 0.0000258 AC XY: 18 AN XY: 698688

African (AFR) AF: 0.00 AC: 0 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: 0.0000699 AC: 6 AN: 85816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47982

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

European-Non Finnish (NFE) AF: 0.0000158 AC: 17 AN: 1075676

Other (OTH) AF: 0.0000529 AC: 3 AN: 56672

GnomAD4 genome AF: 0.0000216 AC: 3 AN: 138874 Hom.: 0 Cov.: 29 AF XY: 0.0000450 AC XY: 3 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: 0.0000304 AC: 2 AN: 65768

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.38
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.17
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.039	D
Polyphen		0.99	D
Vest4		0.26
MutPred		0.69		Loss of stability (P = 0.1037)
MVP		0.81
MPC		0.13
ClinPred		0.097	T
GERP RS		-0.97
PromoterAI		-0.039	Neutral
Varity_R		0.65
gMVP		0.30
Mutation Taster		=86/14	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;