Variant classification summary

NM_000769.4:c.681G>A

CYP2C19 · NP_000760.1:p.(Pro227=) · NM_000769.4

GRCh37: chr10:96541616 G>A · GRCh38: chr10:94781859 G>A

Gene: CYP2C19 Transcript: NM_000769.4

Final call

Benign

PS3 moderate PP3 supporting BA1 stand-alone benign

Variant details

Gene

CYP2C19

Transcript

NM_000769.4

Protein

NP_000760.1:p.(Pro227=)

gnomAD AF

0.1602339404880087 (v4.1)

ClinVar

other

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 moderate: c.681G>A caused aberrant splicing, a premature stop, and a truncated non-functional protein.

2

PP3 supporting: SpliceAI max delta 0.994 predicts splice disruption.

3

BA1: gnomAD v4.1 allele frequency 0.160234 exceeds the 0.05 stand-alone benign threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback rules, BA1 alone establishes Benign; the applied PS3 moderate and PP3 supporting criteria do not satisfy a pathogenic rule, so the evidence is not conflicting.

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 synonymous variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a synonymous variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no documented affected patient with confirmed maternity and paternity, absent family history, and a de novo c.681G>A finding.
PS3	Met	Met at moderate strength: c.681G>A caused aberrant splicing, a premature stop 20 amino acids downstream, and a truncated non-functional protein in the study.	PMID:8195181
PS4	Not assessed	Not assessed: no verified affected/control counts or odds ratio with 95% CI were available to test OR >5.0 with confidence interval excluding 1.0.	PMID:27026020 PMID:27981572
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a synonymous variant.	generic_acmg_combination_rules
PM2	Not met	Not met: gnomAD v4.1 shows AF=0.160234 with 20,742 homozygotes, far above the <=0.0001 PM2 supporting threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation, pathogenic second allele, or parental/offspring testing establishes that c.681G>A is in trans.	clinvar
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a synonymous variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a synonymous variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no affected-patient report establishes c.681G>A as assumed de novo without confirmed parental testing.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or disease-specific co-segregation data are reported for c.681G>A.
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a synonymous variant.	generic_acmg_combination_rules
PP3	Met	Met at supporting: SpliceAI max delta 0.994 exceeds the >=0.2 PP3 supporting threshold.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype or family history is available to test whether it is highly specific for a disease with a single genetic etiology.
PP5	Not met	Not met: no exact-variant ClinVar expert-panel or other qualifying source reports c.681G>A as pathogenic; available submissions are drug-response or likely benign.	clinvar PMID:21716271
BA1	Met	Met: gnomAD all-comers allele frequency is 0.160234 in v4.1, exceeding the 0.05 stand-alone BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not assessed	Not assessed: frequency is 0.160234, but no disorder prevalence, penetrance, allelic heterogeneity, or maximum-credible-frequency calculation supports a disorder-specific BS1 call.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 20,742 homozygotes, but age, health status, and a fully penetrant early-onset CYP2C19 disorder are not established.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific assay demonstrates an absence of damaging effects on CYP2C19 protein function or splicing.
BS4	Not assessed	Not assessed: no affected relatives are documented who lack c.681G>A, so a lack of segregation cannot be established.
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a synonymous variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no individual-level observation shows c.681G>A in trans or cis with a documented pathogenic variant.	clinvar
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a synonymous variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: SpliceAI max delta 0.994 exceeds the <=0.1 BP4 supporting threshold and predicts splice impact.	spliceai
BP5	Not assessed	Not assessed: no disease case is documented in which this variant co-occurs with an independently established alternate molecular basis.
BP6	Not met	Not met: the only likely-benign exact-variant ClinVar assertion is non-expert, with no expert-panel benign or likely-benign classification.	clinvar
BP7	Not met	Not met: the synonymous variant has SpliceAI max delta 0.994, contradicting BP7's required prediction of no splice impact.	spliceai

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.