NM_000762.6:c.1239C>T

Variant names:

• chr19-40844695-G-A
• rs143336165
• NM_000762.6:c.1239C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_000762.6(CYP2A6):​c.1239C>T​(p.Pro413Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000572 in 1,611,738 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00077 (11 hom., cov: 31)
  • Exomes 𝑓: 0.00055 (64 hom.)
• Consequence: CYP2A6 NM_000762.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.16
• Publications: 2 publications found

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]

CYP2A6 Gene-Disease associations (from GenCC):

• coumarin resistance

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)
• nicotine dependence

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000268797 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-40844695-G-A is Benign according to our data. Variant chr19-40844695-G-A is described in ClinVar as [Benign]. Clinvar id is 719052.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.16 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 11 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2A6	NM_000762.6	c.1239C>T	p.Pro413Pro	synonymous_variant	Exon 8 of 9	ENST00000301141.10	NP_000753.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2A6	ENST00000301141.10	c.1239C>T	p.Pro413Pro	synonymous_variant	Exon 8 of 9	1	NM_000762.6	ENSP00000301141.4
ENSG00000268797	ENST00000601627.1	n.117+43280G>A		intron_variant	Intron 1 of 3	3		ENSP00000469533.1
CYP2A6	ENST00000599960.1	n.158C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2
CYP2A6	ENST00000596719.5	n.*227C>T		downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.000773 AC: 117 AN: 151382 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.0159

Gnomad SAS AF: 0.000629

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00170 AC: 426 AN: 251140 AF XY: 0.00156

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00744

Gnomad EAS exome AF: 0.0176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000552 AC: 806 AN: 1460240 Hom.: 64 Cov.: 32 AF XY: 0.000559 AC XY: 406 AN XY: 726428

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

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

Ashkenazi Jewish (ASJ) AF: 0.00769 AC: 201 AN: 26134

East Asian (EAS) AF: 0.0121 AC: 464 AN: 38434

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111930

Other (OTH) AF: 0.00146 AC: 88 AN: 60284

GnomAD4 genome AF: 0.000766 AC: 116 AN: 151498 Hom.: 11 Cov.: 31 AF XY: 0.000851 AC XY: 63 AN XY: 74006

African (AFR) AF: 0.0000242 AC: 1 AN: 41252

American (AMR) AF: 0.000197 AC: 3 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.0157 AC: 78 AN: 4960

South Asian (SAS) AF: 0.000629 AC: 3 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67958

Other (OTH) AF: 0.00286 AC: 6 AN: 2098

Alfa AF: 0.000572 Hom.: 0

Bravo AF: 0.000918

Asia WGS AF: 0.00731 AC: 26 AN: 3432

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.6
DANN	Benign	0.38
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143336165; hg19: chr19-41350600;