19-41004133-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000767.5(CYP2B6):c.304G>T(p.Ala102Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000459 in 1,543,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: CYP2B6 NM_000767.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.380

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.090845704).
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2B6	NM_000767.5	c.304G>T	p.Ala102Ser	missense_variant	2/9	ENST00000324071.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2B6	ENST00000324071.10	c.304G>T	p.Ala102Ser	missense_variant	2/9	1	NM_000767.5	P1
CYP2B6	ENST00000593831.1	c.76G>T	p.Ala26Ser	missense_variant	1/5	2
CYP2B6	ENST00000598834.2	c.208G>T	p.Ala70Ser	missense_variant, NMD_transcript_variant	2/10	5

Frequencies

GnomAD3 genomes AF: 0.000130 AC: 18 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: 0.000258

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000915 AC: 23 AN: 251264 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135792

Gnomad AFR exome AF: 0.000123

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: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000492 AC: 691 AN: 1404986 Hom.: 0 Cov.: 34 AF XY: 0.000462 AC XY: 323 AN XY: 698688

Gnomad4 AFR exome AF: 0.0000314

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000292

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.0000208

Gnomad4 NFE exome AF: 0.000628

Gnomad4 OTH exome AF: 0.000194

GnomAD4 genome AF: 0.000130 AC: 18 AN: 138874 Hom.: 0 Cov.: 29 AF XY: 0.000105 AC XY: 7 AN XY: 66632

Gnomad4 AFR AF: 0.0000267

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000258

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000160 Hom.: 0

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.000296

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

Aug 10, 2023

The c.304G>T (p.A102S) alteration is located in exon 2 (coding exon 2) of the CYP2B6 gene. This alteration results from a G to T substitution at nucleotide position 304, causing the alanine (A) at amino acid position 102 to be replaced by a serine (S). 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	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.011	T;T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.12	N
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.091	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
Polyphen		0.38	B;B;.
Vest4		0.055, 0.083
MVP		0.69
MPC		0.11
ClinPred		0.040	T
GERP RS		-0.97
Varity_R		0.66
gMVP		0.30

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: rs148009906; hg19: chr19-41510038;