The CYP2D6 NM_000106.6:c.506-1G>A (NP_000097.3:p.?) splicing variant has previously been reported in somatic cancers (COSMIC; COSV62243440, n = 12 times). Experimental evidence: The exact variant was reported to cause aberrant 3' splice-site recognition and a predicted frameshift/truncating consequence. Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.CYP2D6 encodes a cytochrome P450 enzyme that helps the body process many medicines, including antidepressants, antipsychotics, pain relievers, cough medicines, heart medicines, and anti-nausea drugs. Common genetic differences and changes in gene copy number can make people process these medicines slowly, normally, or very quickly, affecting drug response and side effects. CYP2D6 is not known to have a specific cancer-causing or cancer-protective role.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, very strong: the canonical -1 splice variant skips 161 coding nucleotides in internal exon 4 of 9, predicting a frameshift subject to nonsense-mediated decay.
Met at supporting strength: the exact variant was reported to cause aberrant 3' splice-site recognition and a predicted frameshift/truncating consequence.
Met: gnomAD v4.1 grpmax FAF is 0.18481171, exceeding the 0.05 BA1 threshold with adequate observed-allele support.
Met at supporting strength: SpliceAI maximum delta 0.005 is below the BP4 cutoff of <=0.1 for this canonical splice-site variant.
VUS: PVS1 (very strong) plus PS3 (supporting) satisfy a pathogenic rule, while BA1 (stand-alone benign) satisfies a benign rule under generic ACMG/AMP fallback.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 257,187 / 1,578,198 alleles. Recorded AF 0.162962. Recorded homozygote count 9043.
This variant is present in gnomAD v2.1 (AF= 0.138417; MAF= 13.84168%, 29026/209700 alleles, homozygotes = 2670) and has highest observed frequency in the European (non-Finnish) population (AF= 0.195948; MAF= 19.59479%, 17283/88202 alleles, homozygotes = 1825); grpmax FAF= 0.194193.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.005. Refer to the recorded PP3/BP4 rationale for interpretation.
1 other · 1 Likely benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV62243440, n = 12 times).
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 5 not met · 11 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PS2, PM6, PP1, and BS4 are not assessed because the available evidence provides no proband-level de novo documentation, parental testing, pedigree, informative meioses, or affected-relative genotype-phenotype data.
No VCEP covers CYP2D6; generic ACMG/AMP 2015 rules govern.
The reviewed exact-variant literature does not provide PS4 case-control enrichment, and the case evidence lacks the phenotype, family-history, and alternate-molecular-diagnosis facts needed for PP4 or BP5.
ClinVar does not show an exact-variant expert-panel pathogenic or benign classification; single-laboratory and non-expert assertions are excluded from PP5 and BP6 by the specified rules.
The variant is a canonical splice-site/intronic variant; generic PP3 and BP4 therefore use only SpliceAI, with no double-counting of other predictor scores.
SpliceAI maximum delta 0.005 does not meet PP3 but meets BP4 at supporting strength under the supplied generic thresholds.
BA1 is met from the gnomAD v4.1 filtering grpmax FAF of 0.18481171, using the required adequate-allele-count metric rather than a small-subgroup popmax point estimate.
BS1 is not assessed because a disorder-specific maximum credible allele-frequency calculation is unavailable for the common CYP2D6 pharmacogenetic phenotype.
BS2 is not assessed because aggregate homozygote counts do not establish healthy adult status or full early-age penetrance.
PM2 is not met because the variant is common in gnomAD all-comers and non-cancer subsets.
No criteria match.
NM_000106.6:c.506-1G>A is a canonical splice-acceptor variant at the -1 position. The affected transcript is the clinically relevant CYP2D6 transcript, and the variant assessment identifies exon 4 of 9 as affected; exon skipping would remove 161 coding nucleotides, which is not divisible by 3 and therefore predicts a frameshift and premature termination. Exon 4 is internal rather than the last or penultimate exon, so the predicted loss-of-function transcript is expected to be subject to nonsense-mediated decay rather than to escape it. The gene-level assessment supports CYP2D6 loss of function as a germline disease mechanism, satisfying the gene eligibility requirement. No named downgrade rule is supported: the affected exon is not a distal terminal exon, no NMD escape is indicated, and no evidence identifies the exon as non-critical or enriched for population loss-of-function variation. The canonical splice-site consequence therefore meets PVS1 at full strength, recorded as the literal strength tier "very strong".
PVS1: Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
PMID:1978565 investigated the exact CYP2D6 intron 3 splice-site variant corresponding to NM_000106.6:c.506-1G>A and reported aberrant 3' splice-site recognition with a downstream frameshift/truncating consequence. This is direct variant-specific functional evidence supporting a damaging effect on CYP2D6 splicing, but the available record does not establish reproducibility in a validated clinical diagnostic laboratory or provide sufficient assay-control detail for a higher strength.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
BA1 is met under the generic ACMG/AMP threshold. The default all-comers gnomAD v4.1 record is appropriate because no VCEP specifies a non-cancer or exome-only source. The filtering allele frequency, grpmax FAF, is 0.18481171 (18.481171%), well above the 0.05 threshold, and the contributing population data exceed the minimum 2,000 observed-allele requirement. The Amish popmax point estimate of 0.238307 is not used for the decision because its 898 observed alleles are below that minimum; the decision rests on grpmax FAF.
BA1: Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
The variant is a canonical splice-site/intronic variant, so the applicable generic BP4 path is SpliceAI only; REVEL is not applicable. SpliceAI maximum delta is 0.005, which is at or below the supplied BP4 supporting cutoff of <= 0.1, supporting no predicted splice impact at supporting strength. This computational result is not combined with the BayesDel score, which has no established generic ACMG-strength calibration.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... Intronic, synonymous, or splice-region variant -> SpliceAI only. There is no REVEL score to fall back to. ... BP4 (supporting): <= 0.1 — SpliceAI recommended cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)
Generic ACMG/AMP PS4 requires significantly increased prevalence in affected individuals versus controls; the supplied generic note specifies RR or OR >5.0 with a confidence interval that excludes 1.0. The literature packet's only ai_classified_papers entry, PMID:1978565, was verified against its available abstract/title as a functional study of the exact CYP2D6 splice variant in an individual with deficient debrisoquine metabolism, not a case-control comparison. The reviewed paper extracts likewise contain no variant-specific case-control counts, affected-versus-unaffected frequencies, OR, RR, or confidence interval. The available gnomAD frequencies are population data only and cannot establish affected-case enrichment. Therefore PS4 is not met.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM2 is not met because the variant is common in population controls. No governing VCEP specifies a non-cancer or exome-only source, so the default all-comers data apply; the gnomAD v4.1 filtering grpmax FAF is 0.18481171, far above the generic PM2 supporting threshold of 0.0001. The non-cancer datasets independently show the same conclusion: gnomAD v2.1 non-cancer exomes AF=0.137409 and gnomAD v3.1 non-cancer genomes AF=0.140401.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
The variant is a canonical splice-site/intronic variant, so the applicable generic PP3 path is SpliceAI only; REVEL is not applicable and the BayesDel score is not usable because no generic ACMG-strength calibration is established. SpliceAI maximum delta is 0.005, below the supplied PP3 supporting threshold of >= 0.2 and therefore below the moderate threshold of >= 0.5. The available splice prediction does not support PP3.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) ... Intronic, synonymous, or splice-region variant -> SpliceAI only. There is no REVEL score to fall back to. ... PP3 (supporting): >= 0.2 — SpliceAI recommended cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)
Generic PP5 requires a reputable recent report of the variant as pathogenic when the evidence is unavailable for independent evaluation. The exact-variant ClinVar record has no expert-panel submissions; it contains a laboratory Likely benign submission and other/drug-response submissions, not an exact-variant expert-panel Pathogenic or Likely pathogenic classification. Ordinary laboratory submissions, aggregate labels, and non-expert assertions do not satisfy the required PP5 trigger. Therefore PP5 is not met.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
Generic BP6 requires a reputable recent benign report when the evidence is unavailable for independent evaluation. The exact-variant ClinVar record has no expert-panel submissions and its Likely benign assertion is from a single clinical laboratory, while other submissions are drug response or other. Under the specified generic rule, ordinary laboratory submissions, aggregate labels, and non-expert assertions must not trigger BP6. Therefore BP6 is not met.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
No case-level proband phenotype, family-history statement, or parental testing result is documented for NM_000106.6:c.506-1G>A. Therefore, de novo status cannot be established, and neither maternity nor paternity confirmation is available to satisfy PS2.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The generic PM3 definition is applicable because CYP2D6 deficient drug-metabolism phenotypes are described as autosomal recessive. However, the available case evidence does not document an affected proband with NM_000106.6:c.506-1G>A, a pathogenic second allele, or parental/offspring testing establishing that the alleles are in trans. Therefore, PM3 cannot be assessed.
For recessive disorders, detected in trans with a pathogenic variant
No case-level report establishes that NM_000106.6:c.506-1G>A arose de novo, and no proband phenotype or parental testing information is provided. The available literature concerns CYP2D6 pharmacogenetic or functional observations rather than an unconfirmed de novo occurrence of this variant.
Assumed de novo, but without confirmation of paternity and maternity.
No affected family members, informative meioses, genotype results in relatives, or phenotype concordance across a family are documented for NM_000106.6:c.506-1G>A. Consequently, co-segregation cannot be assessed or assigned.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The generic PP4 rule requires a patient's phenotype or family history highly specific for a disease with a single genetic etiology. The case evidence supplied for this group provides no patient phenotype, disease diagnosis, or family-history description for this variant; the available literature concerns drug-metabolism or tamoxifen pharmacogenetics rather than a highly specific single-etiology disease phenotype. PP4 cannot be assessed without phenotype or family-history data.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
The allele frequency is high, but BS1 requires that it be greater than expected for the specific disorder rather than merely above the generic 1% default. This CYP2D6 variant is a common pharmacogenetic loss-of-function allele, and the available evidence does not establish a disease prevalence, penetrance, allelic heterogeneity model, or maximum credible allele-frequency calculation for a specific disorder. Therefore BS1 is not assessed from the default alone.
Allele frequency is greater than expected for the disorder. ... BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
The population databases report many homozygotes, including 9043 in gnomAD v4.1, but they do not document that a named individual carrying the variant was a healthy adult, nor do they establish that full penetrance at an early age is expected for a defined CYP2D6 disorder. Aggregate homozygote counts therefore cannot satisfy 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.
No variant-specific functional study in the reviewed evidence demonstrates that NM_000106.6:c.506-1G>A has no damaging effect on CYP2D6 protein function or splicing. The available functional evidence instead supports abnormal splicing, so it cannot support BS3.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
No affected family members carrying or lacking NM_000106.6:c.506-1G>A are described, so there is no documented non-segregation to evaluate. The absence of family data cannot establish BS4 or permit assessment of phenocopies or additional pathogenic variants in the family.
Lack of segregation in affected members of a family.
The generic BP2 definition permits assessment for a fully penetrant dominant disorder when the variant is in trans with a pathogenic variant, or for any inheritance pattern when it is in cis with a pathogenic variant. The available case evidence documents neither a trans nor a cis observation involving NM_000106.6:c.506-1G>A and a pathogenic variant. Therefore, BP2 cannot be assessed.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Generic BP5 requires the variant to be found in a case with an alternate molecular basis for disease. The supplied evidence does not provide a disease case description or an alternate molecular diagnosis for the individual carrying NM_000106.6:c.506-1G>A. Drug-response and population records do not establish an alternate molecular basis for disease, so BP5 cannot be assessed.
Variant found in a case with an alternate molecular basis for disease.
PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_000106.6:c.506-1G>A in CYP2D6 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000097.3:p.?. As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PS1 for CYP2D6, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_000106.6:c.506-1G>A in CYP2D6 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000097.3:p.?. As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM1 for CYP2D6, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000106.6:c.506-1G>A in CYP2D6 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000097.3:p.?. As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for CYP2D6, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_000106.6:c.506-1G>A in CYP2D6 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000097.3:p.?. As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM5 for CYP2D6, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_000106.6:c.506-1G>A in CYP2D6 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000097.3:p.?. As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PP2 for CYP2D6, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_000106.6:c.506-1G>A in CYP2D6 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000097.3:p.?. As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP1 for CYP2D6, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000106.6:c.506-1G>A in CYP2D6 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000097.3:p.?. As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for CYP2D6, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000106.6:c.506-1G>A in CYP2D6 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000097.3:p.?. As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for CYP2D6, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in CYP2D6, mapped onto the exon structure of NM_000106.6. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Amish214 / 898 | 0.2429 hom |
| European (non-Finnish)215160 / 1,160,082 | 0.197090 hom |
| Ashkenazi Jewish5115 / 28,966 | 0.18296 hom |
| Remaining individuals9057 / 61,150 | 0.15410 hom |
| Admixed American6405 / 54,812 | 0.12292 hom |
| European (Finnish)6289 / 62,010 | 0.1240 hom |
| South Asian8810 / 87,366 | 0.1367 hom |
| Middle Eastern589 / 5,978 | 0.09919 hom |
| African/African American5415 / 73,310 | 0.074295 hom |
| East Asian133 / 43,626 | 0.0035 hom |
| European (non-Finnish)17283 / 88,202 | 0.21825 hom |
| Ashkenazi Jewish1649 / 9,086 | 0.18160 hom |
| Remaining individuals911 / 5,902 | 0.1586 hom |
| Admixed American3035 / 27,340 | 0.11197 hom |
| South Asian2540 / 24,506 | 0.1172 hom |
| European (Finnish)2095 / 20,914 | 0.1110 hom |
| African/African American1464 / 18,270 | 0.08120 hom |
| East Asian49 / 15,480 | 0.0032 |
This variant is present in gnomAD v4.1 (AF= 0.162962; MAF= 16.29624%, 257187/1578198 alleles, homozygotes = 9043) and has highest observed frequency in the Amish population (AF= 0.238307; MAF= 23.83073%, 214/898 alleles, homozygotes = 29); grpmax FAF= 0.184812.
This variant is present in gnomAD v2.1 (AF= 0.138417; MAF= 13.84168%, 29026/209700 alleles, homozygotes = 2670) and has highest observed frequency in the European (non-Finnish) population (AF= 0.195948; MAF= 19.59479%, 17283/88202 alleles, homozygotes = 1825); grpmax FAF= 0.194193.
Not available in gnomAD-Canada v1.0.
The variant is a canonical splice-site/intronic variant, so the applicable generic BP4 path is SpliceAI only; REVEL is not applicable. SpliceAI maximum delta is 0.005, which is at or below the supplied BP4 supporting cutoff of <= 0.1, supporting no predicted splice impact at supporting strength. This computational result is not combined with the BayesDel score, which has no established generic ACMG-strength calibration.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... Intronic, synonymous, or splice-region variant -> SpliceAI only. There is no REVEL score to fall back to. ... BP4 (supporting): <= 0.1 — SpliceAI recommended cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)
The variant is a canonical splice-site/intronic variant, so the applicable generic PP3 path is SpliceAI only; REVEL is not applicable and the BayesDel score is not usable because no generic ACMG-strength calibration is established. SpliceAI maximum delta is 0.005, below the supplied PP3 supporting threshold of >= 0.2 and therefore below the moderate threshold of >= 0.5. The available splice prediction does not support PP3.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) ... Intronic, synonymous, or splice-region variant -> SpliceAI only. There is no REVEL score to fall back to. ... PP3 (supporting): >= 0.2 — SpliceAI recommended cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000106.6:c.506-1G>A in CYP2D6 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000097.3:p.?. As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for CYP2D6, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = -0.0238629.
10 paper records listed. 1 cited in the classification.
The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934----A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3' splice recognition site.
Location Article title
Context Variant-specific molecular study of a CYP2D6 allele from an individual with deficient debrisoquine metabolism, including sequence analysis and assessment of aberrant splice recognition.
CYP2D6-mediated metabolism is the rate-limiting enzymatic step for the formation of endoxifen, the most abundant active metabolite.
Introduction, paragraph 1
There was a strong gene-dose effect for an association between the CYP2D6 activity score and endoxifen concentrations (P<10−40) in all ethnic cohorts (Figure 3a).
Results, “Tamoxifen metabolite profiling, compliance and CYP2D6 activity”
The CYP2D6 gene is highly polmorphic. CYP2D6 has over 100 distinct variants, and frequent gene duplications and deletions.
Section 2, “CYP2D6 and Tamoxifen Metabolism,” page 69
All variants passing QC in VCFs from TCGA and ICGC cancer patients were analyzed with the Shannon pipeline 19.
Dataset validation and discussion
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.162962; MAF= 16.29624%, 257187/1578198 alleles, homozygotes = 9043) and has highest observed frequency in the Amish population (AF= 0.238307; MAF= 23.83073%, 214/898 alleles, homozygotes = 29); grpmax FAF= 0.184812.
This variant is present in gnomAD v2.1 (AF= 0.138417; MAF= 13.84168%, 29026/209700 alleles, homozygotes = 2670) and has highest observed frequency in the European (non-Finnish) population (AF= 0.195948; MAF= 19.59479%, 17283/88202 alleles, homozygotes = 1825); grpmax FAF= 0.194193.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as other (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 16889)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = -0.0238629.
This variant has previously been reported in somatic cancers (COSMIC; COSV62243440, n = 12 times).