rs571335587

Variant names:

• chr19-40848304-C-A
• rs571335587
• NM_000762.6:c.569G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-40848304-C-A
• chr19-40848304-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000762.6(CYP2A6):​c.569G>T​(p.Arg190Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000454 in 1,611,882 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00048 (28 hom.)
• Consequence: CYP2A6 NM_000762.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.59

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]

ENSG00000268797 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.067304075).
• BP6: Variant 19-40848304-C-A is Benign according to our data. Variant chr19-40848304-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 739786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2A6	NM_000762.6	c.569G>T	p.Arg190Leu	missense_variant	Exon 4 of 9	ENST00000301141.10	NP_000753.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2A6	ENST00000301141.10	c.569G>T	p.Arg190Leu	missense_variant	Exon 4 of 9	1	NM_000762.6	ENSP00000301141.4
ENSG00000268797	ENST00000601627.1	n.118-43687C>A		intron_variant	Intron 1 of 3	3		ENSP00000469533.1

Frequencies

GnomAD3 genomes AF: 0.000244 AC: 37 AN: 151454 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00753

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000972 AC: 244 AN: 251158 AF XY: 0.00139

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000475 AC: 694 AN: 1460316 Hom.: 28 Cov.: 32 AF XY: 0.000698 AC XY: 507 AN XY: 726468

⚠️ 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: 33458

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000156 AC: 6 AN: 38442

South Asian (SAS) AF: 0.00771 AC: 664 AN: 86142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111974

Other (OTH) AF: 0.000332 AC: 20 AN: 60290

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000244 AC: 37 AN: 151566 Hom.: 0 Cov.: 31 AF XY: 0.000405 AC XY: 30 AN XY: 74036

African (AFR) AF: 0.00 AC: 0 AN: 41264

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 4958

South Asian (SAS) AF: 0.00754 AC: 36 AN: 4772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000236 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.00113 AC: 137

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.83
MutPred		0.90		Gain of ubiquitination at K194 (P = 0.0719);
MVP		0.46
MPC		0.15
ClinPred		0.28	T
GERP RS		2.7
gMVP		0.55
Mutation Taster		=94/6	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

Publications

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Other links and lift over

dbSNP: rs571335587; hg19: chr19-41354209;