chr19-40846030-A-G

Position:

• chr19-40846030-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_000762.6(CYP2A6):​c.899T>C​(p.Ile300Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 1,611,506 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00040 (11 hom.)
• Consequence: CYP2A6 NM_000762.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.471

Genes affected

CYP2A6 (HGNC:2610): (cytochrome P450 family 2 subfamily A member 6) This gene, CYP2A6, 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 hydroxylate coumarin, and also metabolizes nicotine, aflatoxin B1, nitrosamines, and some pharmaceuticals. Individuals with certain allelic variants are said to have a poor metabolizer phenotype, meaning they do not efficiently metabolize coumarin or nicotine. This gene is part of a large cluster of cytochrome P450 genes from the CYP2A, CYP2B and CYP2F subfamilies on chromosome 19q. The gene was formerly referred to as CYP2A3; however, it has been renamed CYP2A6. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a mutagenesis_site Increases phenacetin O-deethylation activity 3 fold. Increases phenacetin O-deethylation activity 8 fold; when associated with A-301. Increases phenacetin O-deethylation activity 10 fold; when associated with S-208 and A-301. Increases phenacetin O-deethylation activity 12 fold; when associated with A-301 and G-369. Increases phenacetin O-deethylation activity 38 fold; when associated with S-208; A-301 and G-369. (size 0) in uniprot entity CP2A6_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.07926196).
• BS2: High AC in GnomAd4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2A6	NM_000762.6	c.899T>C	p.Ile300Thr	missense_variant	6/9	ENST00000301141.10	NP_000753.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2A6	ENST00000301141.10	c.899T>C	p.Ile300Thr	missense_variant	6/9	1	NM_000762.6	ENSP00000301141	P1
CYP2A6	ENST00000596719.5	n.750T>C		non_coding_transcript_exon_variant	5/6	1
CYP2A6	ENST00000600495.1	c.*711T>C		3_prime_UTR_variant, NMD_transcript_variant	6/6	1		ENSP00000472905

Frequencies

GnomAD3 genomes AF: 0.000291 AC: 44 AN: 151136 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000975

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000460

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000843

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000398

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000299 AC: 75 AN: 251126 Hom.: 2 AF XY: 0.000309 AC XY: 42 AN XY: 135734

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000221

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000399 AC: 582 AN: 1460254 Hom.: 11 Cov.: 31 AF XY: 0.000414 AC XY: 301 AN XY: 726440

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000260

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000448

Gnomad4 OTH exome AF: 0.000498

GnomAD4 genome AF: 0.000284 AC: 43 AN: 151252 Hom.: 0 Cov.: 31 AF XY: 0.000298 AC XY: 22 AN XY: 73858

Gnomad4 AFR AF: 0.0000972

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000844

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000398

Gnomad4 OTH AF: 0.000477

Alfa AF: 0.000315 Hom.: 0

Bravo AF: 0.000340

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000585 AC: 2 AN: 3432

EpiCase AF: 0.000491

EpiControl AF: 0.000237

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

Sep 15, 2021

The c.899T>C (p.I300T) alteration is located in exon 6 (coding exon 6) of the CYP2A6 gene. This alteration results from a T to C substitution at nucleotide position 899, causing the isoleucine (I) at amino acid position 300 to be replaced by a threonine (T). 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	0.24
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Benign	0.88
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.10	T
Sift4G	Benign	0.13	T
Vest4		0.23
MVP		0.65
MPC		0.25
ClinPred		0.0068	T
GERP RS		2.4
gMVP		0.25

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: rs148693084; hg19: chr19-41351935;