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GeneBe

19-40844725-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_000762.6(CYP2A6):c.1209T>C(p.Ser403=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00627 in 1,611,118 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0048 ( 9 hom., cov: 31)
Exomes 𝑓: 0.0064 ( 105 hom. )

Consequence

CYP2A6
NM_000762.6 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.84
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.69).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-40844725-A-G is Benign according to our data. Variant chr19-40844725-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2649913.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-40844725-A-G is described in Lovd as [Likely_benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-2.84 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 729 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CYP2A6NM_000762.6 linkuse as main transcriptc.1209T>C p.Ser403= synonymous_variant 8/9 ENST00000301141.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CYP2A6ENST00000301141.10 linkuse as main transcriptc.1209T>C p.Ser403= synonymous_variant 8/91 NM_000762.6 P1
CYP2A6ENST00000599960.1 linkuse as main transcriptn.128T>C non_coding_transcript_exon_variant 1/22

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00482
AC:
729
AN:
151336
Hom.:
9
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00126
Gnomad AMI
AF:
0.00881
Gnomad AMR
AF:
0.0104
Gnomad ASJ
AF:
0.00490
Gnomad EAS
AF:
0.00121
Gnomad SAS
AF:
0.00105
Gnomad FIN
AF:
0.00408
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00631
Gnomad OTH
AF:
0.00481
GnomAD3 exomes
AF:
0.00511
AC:
1284
AN:
251054
Hom.:
21
AF XY:
0.00510
AC XY:
692
AN XY:
135700
show subpopulations
Gnomad AFR exome
AF:
0.00129
Gnomad AMR exome
AF:
0.00599
Gnomad ASJ exome
AF:
0.00506
Gnomad EAS exome
AF:
0.00143
Gnomad SAS exome
AF:
0.000818
Gnomad FIN exome
AF:
0.00615
Gnomad NFE exome
AF:
0.00678
Gnomad OTH exome
AF:
0.00816
GnomAD4 exome
AF:
0.00642
AC:
9373
AN:
1459666
Hom.:
105
Cov.:
32
AF XY:
0.00633
AC XY:
4600
AN XY:
726168
show subpopulations
Gnomad4 AFR exome
AF:
0.00123
Gnomad4 AMR exome
AF:
0.00615
Gnomad4 ASJ exome
AF:
0.00429
Gnomad4 EAS exome
AF:
0.000416
Gnomad4 SAS exome
AF:
0.00105
Gnomad4 FIN exome
AF:
0.00652
Gnomad4 NFE exome
AF:
0.00730
Gnomad4 OTH exome
AF:
0.00607
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00483
AC:
732
AN:
151452
Hom.:
9
Cov.:
31
AF XY:
0.00453
AC XY:
335
AN XY:
73982
show subpopulations
Gnomad4 AFR
AF:
0.00131
Gnomad4 AMR
AF:
0.0104
Gnomad4 ASJ
AF:
0.00490
Gnomad4 EAS
AF:
0.00121
Gnomad4 SAS
AF:
0.00105
Gnomad4 FIN
AF:
0.00408
Gnomad4 NFE
AF:
0.00633
Gnomad4 OTH
AF:
0.00477
Alfa
AF:
0.00310
Hom.:
0
Bravo
AF:
0.00556
EpiCase
AF:
0.00573
EpiControl
AF:
0.00605

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024CYP2A6: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.69
Cadd
Benign
2.0
Dann
Benign
0.50

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs56314118; hg19: chr19-41350630; API