Classification rationale

PM2 BP7 VUS

KMT2A c.2040G>T synonymous · exon 3

PM2 (Supporting): total allele frequency 0.001% in gnomAD, well below the 0.1% threshold, with no homozygotes. BP7 (Supporting): synonymous p.Ser680= deep in exon 3, with no predicted splice impact (SpliceAI max delta 0.006). VUS: the single supporting plus single supporting combination (PM2 + BP7) meets no benign, likely benign, likely pathogenic, or pathogenic rule under generic ACMG/AMP 2015.

PM2 + BP7 → VUS

Gene diagram · NM_005933.3 · variants mapped to exon structure

KMT2A NM_005933.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 17 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (supporting): gnomAD total allele frequency is 0.001%, far below the 0.1% PM2 threshold, with no homozygotes.

Local non-VCEP PM2 threshold: allele frequency <0.1% (absent or extremely low frequency in controls, per ACMG/AMP 2015 PM2 definition, PMID 25741868).gnomAD v2.1 (gnomad_v2): total AF 1.06503e-05 (0.00107%, 3/281,682 alleles), 0 homozygotes; East Asian max subpopulation AF 0.01505%; grpmax FAF 0.00022756 (0.023%) — all below 0.1%.gnomAD v4.1 (gnomad_v4): total AF 1.11571e-05 (0.00112%, 18/1,613,328 alleles), 0 homozygotes; East Asian max subpopulation AF 0.02228%; grpmax FAF 0.00012016 (0.012%) — all below 0.1%.

gnomad_v2 ↗gnomad_v4 ↗

✓

BP7 supporting Benign

Met (supporting): synonymous p.Ser680= deep in exon 3 with SpliceAI max delta 0.006, well below the 0.2 splice-altering threshold.

Variant normalization confirms NM_005933.3:c.2040G>T is synonymous, NP_005924.2:p.(Ser680=), in exon 3 of the KMT2A transcript.SpliceAI (Jaganathan et al. 2019, PMID 30661751; spliceailookup.broadinstitute.org) predicts no splice impact for NM_005933.3:c.2040G>T: max delta 0.006 (DS_AG=0.001, DS_AL=0.0, DS_DG=0.0, DS_DL=0.006), well below the 0.2 splice-altering threshold; no impact on the splice consensus sequence and no creation of an alternate splice site predicted.Variant position c.2040 lies ~1.5 kb from the 5' end and ~1.1 kb from the 3' end of exon 3 (exon span c.503-3156), i.e., not within or near any canonical splice consensus sequence.

spliceai ↗

Assessed · not applied

Pathogenic

PS2 Not assessed: no parental genotyping or trio data were available to confirm a de novo occurrence.

PS3 Not assessed: no functional studies of this variant were available to evaluate a deleterious effect.

PS4 Not assessed: no case-control or affected-versus-control enrichment data were available.

PM6 Not assessed: no proband or parental genotyping data were available to evaluate assumed de novo status.

PP1 Not assessed: no family or segregation data were available to evaluate co-segregation with disease.

PP3 Not met: SpliceAI max delta 0.006 is far below the 0.2 splice-altering threshold, and missense predictors do not apply.

PP4 Not assessed: no proband-level phenotype data were available to evaluate phenotype specificity.

PP5 Not met: no ClinVar expert-panel classification exists for this exact variant; only a single-submitter Likely benign assertion.

Benign

BA1 Not met: allele frequency 0.001% is orders of magnitude below the 1% BA1 threshold.

BS1 Not met: observed allele frequency 0.001% does not exceed the 0.3% BS1 threshold.

BS2 Not met: gnomAD carriers are not phenotype-screened for this early-onset disorder, so unaffected adult status is not demonstrated.

BS3 Not assessed: no well-established functional studies showing no damaging effect were available.

BS4 Not assessed: no family segregation data were available to demonstrate lack of segregation.

BP2 Not met: no observation in trans or cis with a pathogenic variant is documented in any source.

BP4 Not met: no independent BP4 prediction exists beyond the SpliceAI result already applied under BP7.

BP5 Not assessed: no affected carrier is reported in whom an alternate molecular basis could be documented.

BP6 Not met: no ClinVar expert-panel benign assertion exists; a single-submitter Likely benign label does not trigger BP6.

N/A · 9 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.11571e-05; MAF= 0.00112%, 18/1613328 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000222777; MAF= 0.02228%, 10/44888 alleles, homozygotes = 0); grpmax FAF= 0.00012016.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.06503e-05; MAF= 0.00107%, 3/281682 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000150482; MAF= 0.01505%, 3/19936 alleles, homozygotes = 0); grpmax FAF= 0.00022756.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0011% · 18 / 1,613,328
0 hom · FAF 0.012%

East Asian 10 / 44,888	0.022%
Remaining individuals 8 / 62,440	0.013%

+ 8 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

0.0011% · 3 / 281,682
0 hom · FAF 0.023%

East Asian

3 / 19,936

0.015%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 1576960)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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

Triaged references · 1 PMID not cited in assessment

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR