rs186335453

chr19-41004158-G-Cchr19-41004158-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000767.5(CYP2B6):c.329G>C(p.Gly110Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000116 in 858,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G110V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: CYP2B6 NM_000767.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2B6	NM_000767.5	c.329G>C	p.Gly110Ala	missense_variant	2/9	ENST00000324071.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2B6	ENST00000324071.10	c.329G>C	p.Gly110Ala	missense_variant	2/9	1	NM_000767.5	P1
CYP2B6	ENST00000593831.1	c.101G>C	p.Gly34Ala	missense_variant	1/5	2
CYP2B6	ENST00000598834.2	c.233G>C	p.Gly78Ala	missense_variant, NMD_transcript_variant	2/10	5

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250694 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135658

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000116 AC: 1 AN: 858816 Hom.: 0 Cov.: 35 AF XY: 0.00000228 AC XY: 1 AN XY: 438768

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000309

GnomAD4 genome Cov.: 28

Alfa AF: 0.0000169 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.030	T;T;T
Eigen	Benign	0.10
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.0078	T
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	3.0	M;M;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Uncertain	0.51	T
Polyphen		0.94	P;P;.
Vest4		0.45, 0.44
MutPred		0.75		Loss of methylation at R109 (P = 0.0885);Loss of methylation at R109 (P = 0.0885);.;
MVP		0.71
MPC		0.22
ClinPred		0.92	D
GERP RS		1.9
Varity_R		0.71
gMVP		0.38

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: rs186335453; hg19: chr19-41510063;