About H3C2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
H3C2 c.244G>C, p.(Asp82His)
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_003537.3:c.244G>C is absent from gnomAD v2.1 (exomes) and v4.1 (exomes/genomes), as well as gnomAD-Canada v1.0. The allele frequency is 0.0 in all population databases queried, supporting a pathogenic role under PM2.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.080 maximum delta
Recorded SpliceAI maximum delta score: 0.080. 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. H3C2, a histone variant, is recurrently altered by mutation in various pediatric cancers, including pediatric glioblastoma.
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.
26 criteria with recorded statuses: 1 met · 21 not met · 2 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_003537.3:c.244G>C (p.Asp82His) is a missense variant in H3C2, a histone H3 gene recurrently altered in pediatric cancers including glioblastoma.
The variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).
The variant is not present in COSMIC and does not lie within a statistically significant mutational hotspot.
In silico predictions are equivocal: REVEL score is 0.585 and BayesDel is 0.631, both borderline toward pathogenicity, while SpliceAI predicts no splicing impact (max delta 0.08).
No functional studies, segregation data, de novo reports, or case-control evidence have been identified for this variant. OncoKB reports no variant-specific functional evidence.
A single ClinVar submission from Invitae classifies the variant as uncertain significance; no expert panel or multi-submitter consensus is available.
Only one supporting pathogenic criterion (PM2_Supporting) is met. No benign criteria are met. The evidence is insufficient to classify the variant as pathogenic or benign.
No criteria match.
Met · 1
PM2 SupportingNM_003537.3:c.244G>C is absent from gnomAD v2.1 (exomes) and v4.1 (exomes/genomes), as well as gnomAD-Canada v1.0. The allele frequency is 0.0 in all population databases queried, supporting a pathogenic role under PM2. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AC=0
- AN=null — no coverage at this position) and absent from gnomAD v4.1 (AC=0). Also absent from gnomAD-Canada v1.0.
Still missing
- Coverage at this genomic position (6:26032045/26031817) may be limited in gnomAD due to the repetitive histone gene cluster
- absence could reflect technical rather than biological depletion.
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No established pathogenic variant causing the same amino acid change (p.Asp82His) via a different nucleotide substitution has been identified in ClinVar, the literature, or other evidence sources. Details ▾Hide ▴
Evidence considered
- ClinVar contains no pathogenic entry at codon 82 of H3C2 with the Asp82His substitution.
Still missing
- No comprehensive literature screen for all possible nucleotide changes encoding p.Asp82His.
Sources
PS2 No de novo occurrence of NM_003537.3:c.244G>C has been reported. Targeted exploratory literature and ClinVar search identified no de novo designations for any missense at H3C2 codon 82. Details ▾Hide ▴
Evidence considered
- Exploratory search found no de novo reports for H3C2 codon 82 in PubMed or ClinVar
- known histone H3 de novo mutations cluster at K27
- G34
- and K36
- not Asp82.
Still missing
- No parent-of-origin testing data available.
Sources
PS3 No direct functional studies of the H3C2 p.Asp82His substitution have been published. In vitro or in vivo functional characterization of this exact missense change is absent from the literature and curated databases including OncoKB. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional evidence identified. Exploratory review noted only background papers on histone H3 functional domains without Asp82-specific data.
Still missing
- No functional assays (in vitro nucleosome assembly
- chromatin immunoprecipitation
- or cellular assays) have been performed for p.Asp82His.
Sources
PM1 Residue Asp82 lies within the histone fold domain (residues ~45-135), but codon 82 is not a statistically significant mutational hotspot in cancer (Cancer Hotspots database) or germline disease. PM1 requires a mutational hotspot or a well-established critical functional domain without benign variation; Asp82 does not meet this threshold. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: no entry for H3C2 codon 82
- known histone H3 hotspots are K27
- G34
- K36. Histone fold domain is a functional domain but not a recognized mutational hotspot for codon 82.
Still missing
- Residue-level conservation analysis across histone H3 paralogs could further inform functional significance.
PM5 No different missense change at H3C2 codon 82 (Asp82) has been classified as pathogenic. The PM5 candidate search found zero same-residue comparators in ClinVar with pathogenic or likely pathogenic classification. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json: total_candidates_seen=0
- same_residue_candidates=0
- no expert panel PLP comparators.
Sources
pm5_candidates
PM6 No de novo reports exist for NM_003537.3:c.244G>C. ClinVar contains no de novo assertion for this variant, and targeted literature search yielded no case reports with confirmed parentage testing. Details ▾Hide ▴
Evidence considered
- ClinVar variation 2884454 lacks de novo designation
- exploratory literature search found no de novo case reports.
Still missing
- No case reports or clinical testing results indicating de novo occurrence.
Sources
PP1 No familial co-segregation data are available for NM_003537.3:c.244G>C. No pedigrees with multiple affected carriers have been reported in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No segregation data in ClinVar submissions
- exploratory search found no family studies.
Still missing
- No families with multiple affected carriers identified.
Sources
PP3 In silico predictions are borderline and do not provide multiple consistent lines of computational evidence supporting a deleterious effect. REVEL score is 0.585 (marginally above the 0.5 threshold but below commonly used higher thresholds such as 0.75). BayesDel score is 0.631 (modestly in the pathogenic direction). SpliceAI predicts no splicing impact (max delta = 0.08). Taken together, the computational evidence is equivocal and does not meet the PP3 requirement. Details ▾Hide ▴
Evidence considered
- REVEL=0.585 (borderline pathogenic)
- BayesDel=0.631 (modest pathogenic signal)
- SpliceAI max delta=0.08 (no splicing impact).
Still missing
- Additional in silico predictors (CADD
- SIFT
- PolyPhen-2) could be evaluated but are unlikely to change the equivocal picture.
Sources
PP4 No clinical phenotype or family history data specific to this variant are available. The variant has been reported only once in ClinVar (uncertain significance, no phenotype details provided), and no case reports describe the clinical presentation associated with NM_003537.3:c.244G>C. Details ▾Hide ▴
Evidence considered
- Single ClinVar submission (Invitae
- uncertain significance) provides no phenotype information.
Still missing
- No phenotype data available for any individual carrying this variant.
Sources
PP5 No reputable source has classified NM_003537.3:c.244G>C as pathogenic. The only ClinVar submission (Invitae, a single non-expert submitter) classifies it as uncertain significance, which does not meet the PP5 requirement for a reputable source asserting pathogenicity. Details ▾Hide ▴
Evidence considered
- ClinVar: single submitter (Invitae)
- classification: Uncertain Significance. No expert panel or multiple-submitter pathogenic consensus.
Sources
BA1 NM_003537.3:c.244G>C is absent from gnomAD v2.1 and v4.1 (allele frequency = 0). The allele frequency is well below the 1% BA1 threshold. Details ▾Hide ▴
BS1 NM_003537.3:c.244G>C is absent from gnomAD v2.1 and v4.1 (allele frequency = 0). The allele frequency is well below the 0.3% BS1 threshold. Details ▾Hide ▴
BS2 The variant has not been observed in any individual, healthy or affected. No data exist to support observation in a healthy adult with full penetrance expected at an early age. Details ▾Hide ▴
Evidence considered
- Variant absent from all population and clinical databases queried.
Still missing
- No observational data in any individual.
BS3 No functional studies demonstrating that the p.Asp82His substitution has no deleterious effect on protein function have been identified. No in vitro or in vivo assays have been performed for this variant. Details ▾Hide ▴
Evidence considered
- No functional studies available for H3C2 p.Asp82His.
Still missing
- Complete absence of functional characterization.
BS4 No segregation data demonstrating non-segregation of NM_003537.3:c.244G>C with disease are available. No family studies have been reported. Details ▾Hide ▴
Evidence considered
- No segregation data of any kind available.
Still missing
- No families genotyped for this variant.
BP1 BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. For histone H3 genes (including H3C2), the known pathogenic mechanism involves missense mutations at specific residues (K27M, G34R/V, K36M in related paralogs), not truncating variants. Therefore BP1 does not apply. Details ▾Hide ▴
Evidence considered
- Histone H3 disease mechanism is missense-driven
- canonical pathogenic variants (K27M
- G34R
- K36M) are missense
- not truncating.
BP2 The variant has not been observed in any individual, so co-occurrence in trans with a known pathogenic variant cannot be assessed. No data support BP2 application. Details ▾Hide ▴
Evidence considered
- Variant absent from population databases
- no trans co-occurrence data.
Still missing
- No observational data in heterozygous state with any other variant.
BP4 Multiple lines of computational evidence do not support a benign impact. REVEL (0.585) and BayesDel (0.631) both lean in the pathogenic direction, not benign. SpliceAI (max delta 0.08) predicts no splicing impact, but this alone is insufficient to meet BP4 when missense predictors suggest possible deleteriousness. Details ▾Hide ▴
Evidence considered
- REVEL=0.585 (pathogenic direction)
- BayesDel=0.631 (pathogenic direction)
- SpliceAI max delta=0.08 (no splicing impact).
Sources
BP5 No evidence exists that an alternate molecular basis for disease has been identified in any individual carrying NM_003537.3:c.244G>C. The variant has not been observed in any case with a known pathogenic variant at another locus. Details ▾Hide ▴
Evidence considered
- No observational data linking this variant to cases with alternate molecular diagnoses.
Still missing
- No case-level data available.
BP6 No reputable source has classified NM_003537.3:c.244G>C as benign. The only ClinVar submission classifies it as uncertain significance, which does not support BP6. Details ▾Hide ▴
Evidence considered
- ClinVar: single submitter (Invitae)
- classification: Uncertain Significance.
Sources
PS5 No different missense change at codon 82 of H3C2 has been classified as pathogenic. There is no established pathogenic comparator at this residue to support PS5. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json confirms zero same-residue comparator variants with pathogenic classification
- no pathogenic missense at Asp82 in ClinVar.
Sources
clinvar ↗pm5_candidates
Not assessed · 2 · no assessment recorded
PS4 Insufficient data to evaluate case-control enrichment. The variant is absent from gnomAD population databases, and no affected individuals carrying this variant have been reported in disease cohorts or ClinVar (a single ClinVar submission classifies it as uncertain significance with no proband count). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- ClinVar variation 2884454 (single submitter
- Invitae
- Uncertain Significance) with no proband tally.
Still missing
- No case reports or cohort studies enumerating affected individuals with this variant.
Sources
PP2 PP2 requires a gene with a low rate of benign missense variation where missense is a common mechanism of disease. H3C2 missense constraint data (missense Z-score or missense observed/expected ratio) were not available in the evidence bundle. The gnomAD pLI of 0.00 and LOEUF of 0.85 reflect loss-of-function tolerance, which is distinct from missense constraint. This criterion cannot be assessed without a direct missense constraint metric. Details ▾Hide ▴
Evidence considered
- gnomAD pLI=0.00 and LOEUF=0.85 reflect LoF tolerance not missense constraint
- no missense Z-score available.
Still missing
- Requires missense constraint metric (e.g.
- gnomAD missense Z-score or o/e ratio) for H3C2.
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. NM_003537.3:c.244G>C is a missense change (p.Asp82His) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required by the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant
- variant_bucket='other'
- apply_generic_pvs1_framework=false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP7 N/ABP7 is not applicable. NM_003537.3:c.244G>C is a missense variant (p.Asp82His), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous.
Identifiers
- Gene
- H3C2
- Transcript
- NM_003537.3
- Coding (HGVS c.)
- NM_003537.3:c.244G>C
- Protein (HGVS p.)
- NP_003528.1:p.(Asp82His)
- GRCh38
- chr6:26031817 C>G
- GRCh37
- chr6:26032045 C>G
Gene diagram
Every interpreted variant in H3C2, mapped onto the exon structure of NM_003537.3. Select a row to find it on the plot.
H3C2NM_003537.3
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 H3C2
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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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.585
- BayesDel
- 0.631
How the predictions were used
PP3 In silico predictions are borderline and do not provide multiple consistent lines of computational evidence supporting a deleterious effect. REVEL score is 0.585 (marginally above the 0.5 threshold but below commonly used higher thresholds such as 0.75). BayesDel score is 0.631 (modestly in the pathogenic direction). SpliceAI predicts no splicing impact (max delta = 0.08). Taken together, the computational evidence is equivocal and does not meet the PP3 requirement. Details ▾Hide ▴
Evidence considered
- REVEL=0.585 (borderline pathogenic)
- BayesDel=0.631 (modest pathogenic signal)
- SpliceAI max delta=0.08 (no splicing impact).
Still missing
- Additional in silico predictors (CADD
- SIFT
- PolyPhen-2) could be evaluated but are unlikely to change the equivocal picture.
Sources
BP4 Multiple lines of computational evidence do not support a benign impact. REVEL (0.585) and BayesDel (0.631) both lean in the pathogenic direction, not benign. SpliceAI (max delta 0.08) predicts no splicing impact, but this alone is insufficient to meet BP4 when missense predictors suggest possible deleteriousness. Details ▾Hide ▴
Evidence considered
- REVEL=0.585 (pathogenic direction)
- BayesDel=0.631 (pathogenic direction)
- SpliceAI max delta=0.08 (no splicing impact).
Sources
BP7 N/ABP7 is not applicable. NM_003537.3:c.244G>C is a missense variant (p.Asp82His), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.585. BayesDel score = 0.631182.
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.080
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_003537.3%3Ac.244G%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/6-26032045-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr6-26031817-C-G?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_003537.3%3Ac.244G…
- OncoKB ↗www.oncokb.org/gene/H3C2/D82H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=H3C2+c.244G%3EC
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.585. BayesDel score = 0.631182.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. H3C2, a histone variant, is recurrently altered by mutation in various pediatric cancers, including pediatric glioblastoma.
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.