19-41004445-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000767.5(CYP2B6):c.483G>T(p.Lys161Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CYP2B6 NM_000767.5 missense, splice_region
• Scores: Splicing: ADA: 0.004083
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.416

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24642712).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2B6	NM_000767.5	c.483G>T	p.Lys161Asn	missense_variant, splice_region_variant	3/9	ENST00000324071.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2B6	ENST00000324071.10	c.483G>T	p.Lys161Asn	missense_variant, splice_region_variant	3/9	1	NM_000767.5	P1
CYP2B6	ENST00000593831.1	c.255G>T	p.Lys85Asn	missense_variant, splice_region_variant	2/5	2
CYP2B6	ENST00000594187.1	n.67G>T		splice_region_variant, non_coding_transcript_exon_variant	1/2	5
CYP2B6	ENST00000598834.2	c.387G>T	p.Lys129Asn	missense_variant, splice_region_variant, NMD_transcript_variant	3/10	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461548 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727042

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2021

The c.483G>T (p.K161N) alteration is located in exon 3 (coding exon 3) of the CYP2B6 gene. This alteration results from a G to T substitution at nucleotide position 483, causing the lysine (K) at amino acid position 161 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0085	T;T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	0.96	N;N
PrimateAI	Benign	0.26	T
Polyphen		0.59	P;P;.
Vest4		0.18, 0.15
MutPred		0.36		Loss of ubiquitination at K161 (P = 0.0167);Loss of ubiquitination at K161 (P = 0.0167);.;
MVP		0.44
MPC		0.28
ClinPred		0.41	T
GERP RS		2.6
Varity_R		0.31
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0041
dbscSNV1_RF	Benign	0.032
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-41510350;