About KMT2B
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KMT2B c.5989C>G, p.(Leu1997Val)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_014727.2:c.5989C>G is extremely rare in population databases: absent from gnomAD v2.1 and gnomAD-Canada; observed in only 1/1,613,902 alleles (AF=0.00006%) in gnomAD v4.1 with zero homozygotes. This is well below the 0.1% PM2 threshold for a rare variant in a dominant disease gene.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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; combination = 1 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,613,902 alleles
gnomAD v4.1: 1 / 1,613,902 alleles. Recorded AF 6.19616e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KMT2B, a histone methyltransferase, is mutated at low frequencies in various cancer types.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 1 met · 10 not met · 11 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_014727.2:c.5989C>G (p.Leu1997Val) in KMT2B is extremely rare in population databases, observed in only 1 of 1,613,902 alleles (AF=0.00006%) in gnomAD v4.1 and absent from gnomAD v2.1 and gnomAD-Canada, meeting PM2 at supporting strength.
This variant is a missense substitution and does not qualify for PVS1; no pathogenic variants have been reported at the same residue (PS1 not met); no functional studies exist (PS3 not assessed); and no de novo or segregation data are available.
Multiple in silico prediction tools do not support a deleterious effect: REVEL score is 0.37 (intermediate), BayesDel score is -0.166 (benign range), and SpliceAI predicts no splicing impact (max delta=0.00). However, this evidence is mixed and does not confidently meet PP3 or BP4.
The only criterion met is PM2 (supporting). Per ACMG/AMP 2015 classification rules (PMID:25741868), a single supporting pathogenic criterion without any benign criteria is insufficient for a likely pathogenic or benign classification.
Overall classification: Variant of Uncertain Significance (VUS). Additional evidence including functional studies, segregation analysis, case-control data, or clinical correlation is required to resolve the significance of this variant.
No criteria match.
Met · 1
PM2 SupportingNM_014727.2:c.5989C>G is extremely rare in population databases: absent from gnomAD v2.1 and gnomAD-Canada; observed in only 1/1,613,902 alleles (AF=0.00006%) in gnomAD v4.1 with zero homozygotes. This is well below the 0.1% PM2 threshold for a rare variant in a dominant disease gene. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: 1/1
- 613
- 902 alleles (AF=6.20e-7
- 0.00006%)
- 0 homozygotes
- gnomAD-Canada: absent
Sources
Not met · 10 · evaluated, threshold not reached
PS1 No known pathogenic variant at KMT2B residue Leu1997 has been reported in ClinVar or the literature; PS1 requires a different amino acid change at the same residue that is established as pathogenic. Details ▾Hide ▴
Evidence considered
- This variant is absent from ClinVar
- no comparator pathogenic variants at Leu1997 identified
Sources
PM1 This variant does not lie within a statistically significant mutational hotspot, nor within a well-characterized functional domain where pathogenic missense variants cluster and benign variation is absent. Details ▾Hide ▴
Evidence considered
- Hotspots analysis: not in a statistically significant hotspot
- residue_significant=false
PP3 Multiple in silico prediction tools do not support a deleterious effect: REVEL score is 0.37 (below typical pathogenic threshold of >0.5), BayesDel score is -0.166 (benign range), and SpliceAI predicts no splicing impact (max delta=0.00). Details ▾Hide ▴
Evidence considered
- REVEL: 0.37
- BayesDel: -0.166
- SpliceAI max delta: 0.00
Sources
PP5 No reputable source has reported NM_014727.2:c.5989C>G as pathogenic; the variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no expert panel classification available
Sources
BA1 The allele frequency of NM_014727.2:c.5989C>G in gnomAD v4.1 is 0.00006% (6.20e-7), far below the 1% BA1 threshold for a stand-alone benign classification. Details ▾Hide ▴
BS1 The allele frequency of NM_014727.2:c.5989C>G is 0.00006%, far below the 0.3% BS1 threshold. This variant is too rare to be considered a benign polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=6.20e-7 (0.00006%)
- well below BS1 threshold of >0.3%
Sources
BP1 BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease. KMT2B-associated dystonia (DYT28) is known to be caused by both missense and truncating variants, as evidenced by the literature on allelic heterogeneity in KMT2B-associated disease (PMID:29653907). Details ▾Hide ▴
Evidence considered
- KMT2B disease spectrum includes both missense and truncating pathogenic variants
BP4 While SpliceAI predicts no splicing impact (max delta=0.00) and BayesDel falls in the benign range (-0.166), the REVEL score of 0.37 is intermediate and does not confidently exclude pathogenicity. The in silico evidence is mixed rather than uniformly predicting no impact, falling short of the 'multiple lines' threshold required for BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.00 (no splice impact)
- BayesDel: -0.166 (benign range)
- REVEL: 0.37 (intermediate/indeterminate)
Sources
BP5 KMT2B has an established disease association with autosomal dominant dystonia-28 (DYT28, OMIM:617284). BP5 requires the variant to be found in a gene for which disease association has not been established. Details ▾Hide ▴
Evidence considered
- KMT2B is an established disease gene: dystonia-28 (OMIM:617284)
PS5 No reputable source has reported NM_014727.2:c.5989C>G as pathogenic; the variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- This variant is absent from ClinVar
- no reputable source classification available
Sources
Not assessed · 11 · no assessment recorded
PS2 No de novo data are available for NM_014727.2:c.5989C>G; the variant is absent from ClinVar and no publications report this variant. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no publications identified
Still missing
- No parental testing or de novo confirmation available
PS3 No variant-specific functional studies have been reported for NM_014727.2:c.5989C>G. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no curated functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional studies identified
Still missing
- No in vitro or in vivo functional assays available for this variant
Sources
PS4 No case-control or cohort data are available for this variant. The variant is absent from ClinVar and has not been reported in any publication. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no publications identified
Still missing
- No case-control or cohort studies available
PP1 No segregation data are available for this variant; the variant has not been reported in any family studies. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data identified
Still missing
- No segregation analysis available
PP2 KMT2B constraint metrics (gnomAD missense Z-score, o/e ratio) were not retrieved in this case; PP2 assessment requires gene-level constraint data to determine whether the gene has a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
- HCI prior not available (gene_not_supported)
- gnomAD constraint data not retrieved
Still missing
- gnomAD missense Z-score and constraint metrics unavailable
PP4 No patient-specific phenotype or clinical data are available for this variant; PP4 requires that the patient's phenotype or family history is highly specific for KMT2B-related disease. Details ▾Hide ▴
Evidence considered
- No patient phenotype or clinical data provided
Still missing
- Patient phenotype and family history data not available
BS2 One heterozygous carrier is observed in gnomAD v4.1 (European non-Finnish), but the phenotype/health status of this individual is unknown. BS2 requires observation in a healthy adult individual with full penetrance expected at an early age, which cannot be confirmed from gnomAD data alone. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 1 heterozygous carrier (NFE)
- phenotype unknown
Still missing
- Health/phenotype status of the single gnomAD carrier unknown
Sources
BS3 No variant-specific functional studies demonstrating no deleterious effect have been reported for NM_014727.2:c.5989C>G. In silico predictions alone do not constitute functional evidence per ACMG/AMP guidelines. Details ▾Hide ▴
Evidence considered
- No functional studies identified
- in silico predictions are not functional evidence
Still missing
- No in vitro or in vivo functional assays demonstrating normal function
BS4 No segregation data are available to assess lack of cosegregation with disease; the variant has not been reported in any family studies. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data identified
Still missing
- No segregation data available to demonstrate lack of cosegregation
BP2 No data are available regarding a second pathogenic variant in trans or a homozygous state; BP2 requires observation in trans with a pathogenic variant or as homozygous for a recessive disorder. Details ▾Hide ▴
Evidence considered
- No trans or homozygous configuration data available
Still missing
- No data on second variant in trans
BP6 No reputable source has classified NM_014727.2:c.5989C>G as benign; the variant is absent from ClinVar entirely. Details ▾Hide ▴
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_014727.2:c.5989C>G (p.Leu1997Val) is a missense variant and does not fall into the null-variant buckets (nonsense, frameshift, canonical ±1,2 splice consensus) required for generic PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant in exon 28
- variant_bucket='other'
- apply_generic_pvs1_framework=false
Sources
PM3 N/APM3 applies to recessive disorders; KMT2B-associated disease is autosomal dominant. No trans configuration data available. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein-length altering variants (in-frame deletions/insertions, stop-loss); this is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo same-residue pathogenic comparator variants were identified at KMT2B Leu1997; automatic PM5 candidate harvesting found zero candidates. Details ▾Hide ▴
Evidence considered
- pm5_mode=unknown
- 0 same-residue candidates
- recommendation level=not_applicable
Sources
pm5_candidates
PM6 N/ANo de novo data available for NM_014727.2:c.5989C>G; PM6 is not applicable without a confirmed de novo observation. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar or literature
Still missing
- No parental testing data available
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions; this is a substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants without predicted splicing impact. NM_014727.2:c.5989C>G is a missense variant (p.Leu1997Val). Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous
Identifiers
- Gene
- KMT2B
- Transcript
- NM_014727.2
- Coding (HGVS c.)
- NM_014727.2:c.5989C>G
- Protein (HGVS p.)
- NP_055542.1:p.(Leu1997Val)
- GRCh38
- chr19:35732538 C>G
- GRCh37
- chr19:36223439 C>G
Gene diagram
Every interpreted variant in KMT2B, mapped onto the exon structure of NM_014727.2. Select a row to find it on the plot.
KMT2BNM_014727.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in KMT2B
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1 / 1,613,902 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,902 alleles · 0 hom
| European (non-Finnish)1 / 1,179,880 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19616e-07; MAF= 0.00006%, 1/1613902 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47544e-07; MAF= 0.00008%, 1/1179880 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.370
- BayesDel
- -0.166
How the predictions were used
PP3 Multiple in silico prediction tools do not support a deleterious effect: REVEL score is 0.37 (below typical pathogenic threshold of >0.5), BayesDel score is -0.166 (benign range), and SpliceAI predicts no splicing impact (max delta=0.00). Details ▾Hide ▴
Evidence considered
- REVEL: 0.37
- BayesDel: -0.166
- SpliceAI max delta: 0.00
Sources
BP4 While SpliceAI predicts no splicing impact (max delta=0.00) and BayesDel falls in the benign range (-0.166), the REVEL score of 0.37 is intermediate and does not confidently exclude pathogenicity. The in silico evidence is mixed rather than uniformly predicting no impact, falling short of the 'multiple lines' threshold required for BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.00 (no splice impact)
- BayesDel: -0.166 (benign range)
- REVEL: 0.37 (intermediate/indeterminate)
Sources
BP7 N/ABP7 applies to synonymous variants without predicted splicing impact. NM_014727.2:c.5989C>G is a missense variant (p.Leu1997Val). Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.37. BayesDel score = -0.166046.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,613,902 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_014727.2%3Ac.5989C%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-36223439-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-35732538-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-35732538-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_014727.2%3Ac.5989…
- OncoKB ↗www.oncokb.org/gene/KMT2B/L1997V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=KMT2B+c.5989C%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19616e-07; MAF= 0.00006%, 1/1613902 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47544e-07; MAF= 0.00008%, 1/1179880 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.37. BayesDel score = -0.166046.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KMT2B, a histone methyltransferase, is mutated at low frequencies in various cancer types.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.