NM_014727.2:c.5989C>G

KMT2B · NP_055542.1:p.(Leu1997Val) · NM_014727.2

GRCh37: chr19:36223439 C>G · GRCh38: chr19:35732538 C>G

Gene: KMT2B Transcript: NM_014727.2

Final call

VUS

PM2 supporting

Variant details

Gene

KMT2B

Transcript

NM_014727.2

Protein

NP_055542.1:p.(Leu1997Val)

gnomAD AF

6.196163087969406e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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	NM_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).	pvs1_generic_framework
PS1	Not met	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.	clinvar
PS2	Not assessed	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.
PS3	Not assessed	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.	oncokb
PS4	Not assessed	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.
PS5	Not met	No reputable source has reported NM_014727.2:c.5989C>G as pathogenic; the variant is absent from ClinVar entirely.	clinvar
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue pathogenic comparator variants were identified at KMT2B Leu1997; automatic PM5 candidate harvesting found zero candidates.	pm5_candidates
PM6	N/A	No de novo data available for NM_014727.2:c.5989C>G; PM6 is not applicable without a confirmed de novo observation.
PP1	Not assessed	No segregation data are available for this variant; the variant has not been reported in any family studies.
PP2	Not assessed	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.
PP3	Not met	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).	revel bayesdel spliceai
PP4	Not assessed	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.
PP5	Not met	No reputable source has reported NM_014727.2:c.5989C>G as pathogenic; the variant is absent from ClinVar.	clinvar
BA1	Not met	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.	gnomad_v4
BS1	Not met	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.	gnomad_v4
BS2	Not assessed	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.	gnomad_v4
BS3	Not assessed	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.
BS4	Not assessed	No segregation data are available to assess lack of cosegregation with disease; the variant has not been reported in any family studies.
BP1	Not met	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).
BP2	Not assessed	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.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions; this is a substitution variant.
BP4	Not met	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.	spliceai bayesdel revel
BP5	Not met	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.
BP6	Not assessed	No reputable source has classified NM_014727.2:c.5989C>G as benign; the variant is absent from ClinVar entirely.	clinvar
BP7	N/A	BP7 applies to synonymous variants without predicted splicing impact. NM_014727.2:c.5989C>G is a missense variant (p.Leu1997Val).
PM3	N/A	PM3 applies to recessive disorders; KMT2B-associated disease is autosomal dominant. No trans configuration data available.
PM4	N/A	PM4 applies to protein-length altering variants (in-frame deletions/insertions, stop-loss); this is a missense substitution.

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