19-41009358-A-T

Variant names:

• chr19-41009358-A-T
• rs2279343
• NM_000767.5:c.785A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000767.5(CYP2B6):​c.785A>T​(p.Lys262Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. K262R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP2B6 NM_000767.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.784
• Publications: 383 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2B6	NM_000767.5	c.785A>T	p.Lys262Met	missense_variant	Exon 5 of 9	ENST00000324071.10	NP_000758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2B6	ENST00000324071.10	c.785A>T	p.Lys262Met	missense_variant	Exon 5 of 9	1	NM_000767.5	ENSP00000324648.2
CYP2B6	ENST00000598834.2	n.*226A>T		non_coding_transcript_exon_variant	Exon 6 of 10	5		ENSP00000496294.1
CYP2B6	ENST00000598834.2	n.*226A>T		3_prime_UTR_variant	Exon 6 of 10	5		ENSP00000496294.1
CYP2B6	ENST00000593831.1	c.257-2940A>T		intron_variant	Intron 2 of 4	2		ENSP00000470582.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.56e-7 AC: 1 AN: 1322648 Hom.: 0 Cov.: 36 AF XY: 0.00000151 AC XY: 1 AN XY: 661088

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29534

American (AMR) AF: 0.00 AC: 0 AN: 41996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24130

East Asian (EAS) AF: 0.00 AC: 0 AN: 37476

South Asian (SAS) AF: 0.00 AC: 0 AN: 80080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5254

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 998416

Other (OTH) AF: 0.00 AC: 0 AN: 55054

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 2155

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.026	T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.3	L;L
PhyloP100		0.78
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.8	.;D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		0.59	P;P
Vest4		0.19
MutPred		0.57		Loss of methylation at K262 (P = 0.0045);Loss of methylation at K262 (P = 0.0045);
MVP		0.69
MPC		0.38
ClinPred		0.96	D
GERP RS		-1.7
Varity_R		0.54
gMVP		0.38
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2279343; hg19: chr19-41515263;