Variant classification summary

NM_000106.6:c.506-1G>A

CYP2D6 · NP_000097.3:p.? · NM_000106.6

GRCh37: chr22:42524947 C>T · GRCh38: chr22:42128945 C>T

Gene: CYP2D6 Transcript: NM_000106.6

Final call

VUS

PVS1 very strong PS3 supporting BA1 stand-alone benign BP4 supporting

Variant details

Gene

CYP2D6

Transcript

NM_000106.6

Protein

NP_000097.3:p.?

gnomAD AF

0.16296244197496132 (v4.1)

ClinVar

other

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong predicts loss of function from an internal-exon canonical splice variant.

2

Pathogenic: PS3 supporting reports aberrant splicing and a predicted truncating consequence for the exact variant.

3

Benign: BA1 is met because gnomAD v4.1 grpmax FAF is 0.18481171, above 0.05.

4

Benign: BP4 supporting is met because SpliceAI maximum delta is 0.005, below 0.1.

Final determination: Under generic ACMG/AMP 2015 rules, PVS1 very strong plus PS3 supporting satisfies a pathogenic rule and BA1 independently satisfies a benign rule; conflicting evidence therefore yields VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no documented proband disease, family-history information, or confirmed maternity and paternity testing is available for this variant.
PS3	Met	Met at supporting strength: the exact variant was reported to cause aberrant 3' splice-site recognition and a predicted frameshift/truncating consequence.	PMID:1978565
PS4	Not met	Not met: no variant-specific case-control counts, odds ratio, relative risk, or confidence interval demonstrates the required OR >5.0 with a confidence interval excluding 1.0.	PMID:1978565 gnomad_v2 gnomad_v4
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PM2	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.18481171, far above the <=0.0001 PM2 threshold, with similar non-cancer frequencies.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no affected-proband observation or parental/offspring phase evidence shows c.506-1G>A in trans with a pathogenic CYP2D6 allele.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a canonical splice-site variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no documented de novo occurrence is reported, so assumed de novo status without parental confirmation cannot be evaluated.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or family genotype-phenotype segregation data are documented for this variant.
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI maximum delta 0.005 is below the PP3 supporting threshold of >=0.2 for this canonical splice-site variant.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype or family-history description is available to test the required highly specific disease association.
PP5	Not met	Not met: ClinVar has zero expert-panel submissions and no exact-variant expert-panel Pathogenic or Likely pathogenic classification.	clinvar
BA1	Met	Met: gnomAD v4.1 grpmax FAF is 0.18481171, exceeding the 0.05 BA1 threshold with adequate observed-allele support.	gnomad_v4
BS1	Not assessed	Not assessed: frequency is 0.18481171, but disease prevalence, penetrance, allelic heterogeneity, and a maximum-credible-frequency model are unavailable.	gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 9043 homozygotes, but aggregate counts do not establish healthy adult status or full early-age penetrance.	gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific assay shows absence of damage to CYP2D6 function or splicing; available evidence instead reports aberrant splicing.	PMID:1978565
BS4	Not assessed	Not assessed: no affected relatives with documented variant status are available to demonstrate lack of segregation or exclude phenocopies.
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no documented cis or trans observation places c.506-1G>A with a pathogenic variant in an affected or tested individual.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a canonical splice-site variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting strength: SpliceAI maximum delta 0.005 is below the BP4 cutoff of <=0.1 for this canonical splice-site variant.	spliceai
BP5	Not assessed	Not assessed: no disease case and no alternate molecular diagnosis are documented for the individual carrying this variant.
BP6	Not met	Not met: the only benign assertion is a single-laboratory Likely benign submission, not an exact-variant ClinVar expert-panel benign or likely benign classification.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.