19-41004142-G-C

Variant names:

• chr19-41004142-G-C
• rs1435601876
• NM_000767.5:c.313G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000767.5(CYP2B6):​c.313G>C​(p.Asp105His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000802 in 1,246,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: CYP2B6 NM_000767.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.316
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17850131).

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.313G>C	p.Asp105His	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.313G>C	p.Asp105His	missense	Exon 2 of 9	ENSP00000324648.2	P20813-1
	CYP2B6	ENST00000593831.1	TSL:2	c.85G>C	p.Asp29His	missense	Exon 1 of 5	ENSP00000470582.1	M0QZJ2
	CYP2B6	ENST00000863358.1		c.172-2795G>C		intron	N/A	ENSP00000533417.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 8.02e-7 AC: 1 AN: 1246726 Hom.: 0 Cov.: 34 AF XY: 0.00000162 AC XY: 1 AN XY: 618010

African (AFR) AF: 0.00 AC: 0 AN: 27272

American (AMR) AF: 0.00 AC: 0 AN: 38334

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18294

East Asian (EAS) AF: 0.00 AC: 0 AN: 19758

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4642

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 973806

Other (OTH) AF: 0.00 AC: 0 AN: 46068

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions

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	Uncertain	0.41
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.32
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.13
Sift	Benign	0.047	D
Sift4G	Uncertain	0.043	D
Polyphen		0.43	B
Vest4		0.15
MutPred		0.56		Gain of MoRF binding (P = 0.0516)
MVP		0.77
MPC		0.11
ClinPred		0.13	T
GERP RS		1.7
PromoterAI		-0.036	Neutral
Varity_R		0.42
gMVP		0.48
Mutation Taster		=88/12	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: rs1435601876; hg19: chr19-41510047;