Variant classification summary

NM_000771.4:c.1075A>C

CYP2C9 · NP_000762.2:p.(Ile359Leu) · NM_000771.4

GRCh37: chr10:96741053 A>C · GRCh38: chr10:94981296 A>C

Gene: CYP2C9 Transcript: NM_000771.4

Final call

Benign

BA1 stand-alone benign BS1 strong BP4 supporting

Variant details

Gene

CYP2C9

Transcript

NM_000771.4

Protein

NP_000762.2:p.(Ile359Leu)

gnomAD AF

0.06340828681012957 (v4.1)

ClinVar

drug response

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Benign: BA1 is met because gnomAD v4.1 grpmax FAF is 10.8302%, above the 5% stand-alone benign threshold.

2

Benign: BS1 is met because gnomAD v4.1 grpmax FAF is 10.8302%, above the 1% threshold.

3

Benign: BP4 is met at supporting strength because REVEL is 0.07, below the 0.29 cutoff.

Final determination: Under the generic ACMG/AMP 2015 fallback, BA1 alone supports a Benign classification; the additional BS1 strong and BP4 supporting benign criteria are concordant.

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	N/A	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no previously established pathogenic variant with the same p.Ile359Leu amino-acid change is documented; ClinVar reports drug response without assertion criteria.	PMID:28198005 clinvar
PS2	Not assessed	Not assessed: no documented proband phenotype, family-history assessment, or confirmed maternity and paternity is available for this variant.
PS3	Not assessed	Not assessed: CYP2C9*3 is reported to impair S-warfarin metabolism by approximately 80–90%, but primary assay controls and reproducibility details are unavailable.	PMID:28198005
PS4	Not met	Not met: reviewed studies provide pharmacogenetic effects but no affected-versus-control comparison from which the required OR >5.0 and confidence interval excluding 1.0 can be established.	PMID:15805193 PMID:25099164 PMID:28198005
PM1	Not met	Not met: gnomAD v4.1 shows AF 6.34%, grpmax FAF 10.83%, and 3,705 homozygotes, contradicting the required absence of benign variation.	PMID:15805193 gnomad_v4
PM2	Not met	Not met: gnomAD v4.1 total AF is 6.34083% and grpmax FAF is 10.8302%, far above the <=0.01% PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no recessive disease context or parental/offspring phase testing establishes this variant in trans with a pathogenic allele.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different pathogenic missense substitution at residue 359 was identified, but a comprehensive same-residue comparator search remains unavailable.	pm5_candidates PMID:28198005
PM6	Not assessed	Not assessed: no assumed de novo occurrence or parental testing showing the variant absent in either parent is documented.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or variant-positive family members are documented for segregation analysis.
PP2	Not met	Not met: this missense variant has gnomAD v4.1 AF 6.34%, grpmax FAF 10.83%, and 3,705 homozygotes, inconsistent with low benign missense variation.	gnomad_v4
PP3	Not met	Not met: missense REVEL score 0.07 is below the PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family history is available to determine whether the presentation is highly specific for a single-gene disease.
PP5	Not met	Not met: no exact-variant expert-panel pathogenic or likely pathogenic classification was identified; ClinVar contains only a non-expert drug-response submission.	clinvar PMID:25099164 PMID:28198005
BA1	Met	Met: gnomAD v4.1 grpmax FAF is 10.8302%, exceeding the >=5% BA1 threshold with 10,029 observed South Asian alleles.	gnomad_v2 gnomad_v4 clinvar
BS1	Met	Met: gnomAD v4.1 grpmax FAF is 10.8302%, above the generic BS1 threshold of 1%, based on 10,029 observed alleles.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD has 3,705 homozygotes, but no established early-onset, fully penetrant CYP2C9 disorder or phenotype-confirmed healthy-adult observations is provided.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: the available variant-specific evidence reports approximately 80–90% impaired S-warfarin metabolism, not preserved CYP2C9 function.	PMID:28198005
BS4	Not assessed	Not assessed: no affected relatives with documented genotypes and phenotypes are available to evaluate lack of segregation.
BP1	Not assessed	Not assessed: the available evidence does not establish that CYP2C9 disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no documented cis or trans phase observation with a pathogenic variant is available for this variant.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting strength: missense REVEL score 0.07 is below the BP4 supporting cutoff of 0.29.	revel
BP5	Not assessed	Not assessed: no disease case with this variant and an independently established alternate molecular basis was identified.
BP6	Not met	Not met: no exact-variant expert-panel benign or likely benign classification was identified, and the only ClinVar submission reports drug response.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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