MAPK1

Final classification

VUS

MAPK1 c.913G>C · p.Glu305Gln

MAPK1

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.

Gene

MAPK1

Transcript

NM_002745.4

HGVS · transcript:coding

NM_002745.4:c.913G>C

Consequence

N/A

GRCh38

chr22:21772926 C>G

GRCh37

chr22:22127215 C>G

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.

Classification rationale

PM2 BP4 VUS

MAPK1 c.913G>C

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.¹ 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 0.00.² 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).³

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗

3 generic_acmg_combination_rules

Gene diagram · NM_002745.4 · variants mapped to exon structure

MAPK1 NM_002745.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 16 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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.

Absent from gnomAD v2.1 (AF=0)v4.1 (AF=0)and gnomAD-Canada v1.0 (AF=0).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

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, <0.0), SpliceAI max delta score 0.00 (no predicted splice alteration). The preponderance of computational evidence supports a benign interpretation.

REVEL 0.334 (<0.5)BayesDel -0.039 (<0.0)SpliceAI 0.00.

spliceai ↗

Assessed · not applied

Pathogenic

PS2 No de novo data available.

PS3 No variant-specific functional studies identified.

PS4 No case-control comparison or enrichment data available.

PM1 The variant does not lie within a statistically significant mutational hotspot (CancerHotspots: no hotspot at p.Glu305).

PM6 No de novo observation reported.

PP1 No segregation data available.

PP3 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).

PP4 No phenotype specificity data available.

PP5 Variant is absent from ClinVar.

Benign

BA1 Allele frequency is 0.0% across all queried gnomAD populations, well below the BA1 threshold of >1%.

BS1 Allele frequency is 0.0% across all queried gnomAD populations, well below the BS1 threshold of >0.3%.

BS2 No observation in healthy adult controls.

BS3 No functional studies demonstrating a benign effect for this variant.

BS4 No segregation data available showing lack of co-segregation with disease.

BP2 No observation in trans with a known pathogenic variant in a dominantly inherited gene.

BP6 Variant is absent from ClinVar.

N/A · 10 PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP5 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.334. BayesDel score = -0.0393339.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MAPK1 (ERK2), a serine/threonine kinase, is altered by mutation or amplification in various cancer types including head and neck, cervical and ovarian

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Re-run this variant?