NM_002745.4:c.913G>C

MAPK1 · NP_002736.3:p.(Glu305Gln) · NM_002745.4

GRCh37: chr22:22127215 C>G · GRCh38: chr22:21772926 C>G

Gene: MAPK1 Transcript: NM_002745.4

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

MAPK1

Transcript

NM_002745.4

Protein

NP_002736.3:p.(Glu305Gln)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (total allele frequency 0.0), meeting the generic ACMG PM2 threshold of <0.1% in all population databases.

BP4 (Supporting Benign): Multiple in silico tools predict no deleterious effect — REVEL score 0.334 (below 0.5 pathogenic threshold), BayesDel score -0.039 (within benign range), and SpliceAI max delta 0.00.

Classification: Variant of Uncertain Significance (VUS). One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) yield indeterminate evidence per the ACMG/AMP 2015 combination rules (PMID:25741868).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	Missense variant p.(Glu305Gln) at c.913; does not fall into PVS1 null-variant buckets (nonsense, frameshift, canonical ±1,2 splice). Generic PVS1 framework (PMC6185798) is not applicable to missense variants.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No known pathogenic variant with the same amino acid change (p.Glu305Gln) has been reported in ClinVar or identified in the literature. The variant is absent from all queried sources, so no same-change comparator exists.	clinvar
PS2	Not met	No de novo data available. No family-based testing, trio analysis, or confirmed maternity/paternity testing identified for this variant.
PS3	Not met	No variant-specific functional studies identified. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence for p.(Glu305Gln). Literature review returned no functional assays demonstrating a deleterious effect for this variant.	oncokb
PS4	Not met	No case-control comparison or enrichment data available. The variant is absent from gnomAD, but this alone does not satisfy PS4 without a matched disease cohort demonstrating statistically significant enrichment.
PS5	Not assessed	No alternative evidence stream exists for this variant; it is absent from ClinVar and no published functional or case data are available to support an independent assertion of pathogenicity.
PM1	Not met	The variant does not lie within a statistically significant mutational hotspot (CancerHotspots: no hotspot at p.Glu305). No functional domain enrichment data or pathogenic variant cluster is identified at this residue.	oncokb
PM2	Met	Variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Total allele frequency = 0.0, meeting the generic ACMG PM2 threshold of <0.1% in all population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue (p.Glu305) comparator missense variant with an established pathogenic classification could be identified. PM5 candidate harvesting returned zero eligible comparators.	pm5_candidates clinvar
PM6	Not met	No de novo observation reported. No patient with confirmed maternity/paternity testing and de novo status identified for this variant.
PP1	Not assessed	No segregation data available. No family studies or co-segregation analysis with disease phenotype identified for this variant.
PP2	N/A	HCI prior data not available for MAPK1; missense constraint (Z-score) cannot be evaluated. The gene lacks established missense intolerance metrics required for PP2 adjudication.
PP3	Not met	Multiple in silico tools do not support a deleterious effect: REVEL score 0.334 (below 0.5 pathogenic threshold), BayesDel score -0.039 (within benign range). SpliceAI max delta score = 0.00 predicts no splice impact. No computational evidence supports pathogenicity.	revel bayesdel spliceai
PP4	Not met	No phenotype specificity data available. No patient or cohort data linking this specific variant to a well-defined clinical phenotype.
PP5	Not met	Variant is absent from ClinVar. No reputable source has independently classified this variant as pathogenic, and no expert panel assertion of pathogenicity exists.	clinvar
BA1	Not met	Allele frequency is 0.0% across all queried gnomAD populations, well below the BA1 threshold of >1%. This criterion requires a high population frequency incompatible with a rare disease variant.	gnomad_v2 gnomad_v4
BS1	Not met	Allele frequency is 0.0% across all queried gnomAD populations, well below the BS1 threshold of >0.3%. The variant is too rare in population databases to satisfy this benign criterion.	gnomad_v2 gnomad_v4
BS2	Not assessed	No observation in healthy adult controls. No homozygous or hemizygous observations available in population databases to assess against a fully penetrant dominant model.
BS3	Not met	No functional studies demonstrating a benign effect for this variant. No in vitro or in vivo assays evaluating p.(Glu305Gln) have been identified in the literature.
BS4	Not assessed	No segregation data available showing lack of co-segregation with disease. No family studies have been identified for this variant.
BP1	N/A	No other missense variant at the same residue (p.Glu305) with an established pathogenic classification is available for comparison. BP1 requires a known pathogenic missense at the same amino acid position.	pm5_candidates
BP2	Not assessed	No observation in trans with a known pathogenic variant in a dominantly inherited gene. No phase data or co-occurrence data available.
BP3	N/A	Missense substitution; BP3 applies to in-frame insertions/deletions in repetitive regions without a known function.
BP4	Met	Multiple in silico tools predict no deleterious effect: REVEL score 0.334 (below 0.5 pathogenic threshold), BayesDel score -0.039 (within benign range, <0.0), SpliceAI max delta score 0.00 (no predicted splice alteration). The preponderance of computational evidence supports a benign interpretation.	revel bayesdel spliceai
BP5	N/A	No case with an alternative molecular basis for disease has been identified. BP5 requires observation of the variant in a case with an alternative clearly pathogenic cause of disease.
BP6	Not met	Variant is absent from ClinVar. No reputable source has independently classified this variant as benign. No expert panel or clinical laboratory assertion of benignity exists.	clinvar
BP7	N/A	Missense substitution c.913G>C (p.Glu305Gln); BP7 applies exclusively to synonymous (silent) variants predicted to have no splice impact.
PM3	N/A	No observation in trans with a pathogenic variant; recessive inheritance data not available for MAPK1. PM3 is reserved for recessive disorders.
PM4	N/A	Missense substitution; PM4 applies to non-repeat in-frame deletions/insertions and stop-loss variants altering protein length.

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