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H3C2c.290G>CUncertain significance
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Variant interpretation report

H3C2 c.290G>C, p.(Cys97Ser)

NM_003537.3:c.290G>C NP_003528.1:p.(Cys97Ser) View identifiers
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.

About H3C2

No gene-level summary was recorded for this case.

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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

Variant is absent from gnomAD v2.1 (0/251,472 alleles) and near-absent in gnomAD v4.1 (2/1,614,256 alleles; AF=1.24×10⁻⁶), well below the 0.1% PM2 threshold. Also absent from gnomAD-Canada.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest a benign effect: REVEL score 0.117 (below all pathogenic thresholds), BayesDel score −0.262 (benign direction), and SpliceAI max delta 0.05 (no predicted splice impact).

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, BP4 supporting; combination = 1 supporting + 1 supporting benign, 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
2 / 1,614,256 alleles

gnomAD v4.1: 2 / 1,614,256 alleles. Recorded AF 1.23896e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251472 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16256 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.050 maximum delta

Recorded SpliceAI maximum delta score: 0.050. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → 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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 4 not met · 16 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PM2_Supporting is met: variant is absent from gnomAD v2.1 and near-absent in gnomAD v4.1 (2/1,614,256 alleles; AF=1.24×10⁻⁶).

BP4_Supporting is met: multiple in silico tools predict a benign effect — REVEL 0.117, BayesDel −0.262, SpliceAI max delta 0.05.

Under generic ACMG/AMP 2015 combination rules (PMID:25741868), the evidence profile of 1 supporting pathogenic (PM2) and 1 supporting benign (BP4) does not meet the threshold for Likely Pathogenic (requires at least 1 moderate + 4 supporting, or 2 moderate + 2 supporting, etc.) or Likely Benign (requires 2 supporting benign criteria). The variant is classified as Uncertain Significance (VUS).

Met · 2

PM2 SupportingVariant is absent from gnomAD v2.1 (0/251,472 alleles) and near-absent in gnomAD v4.1 (2/1,614,256 alleles; AF=1.24×10⁻⁶), well below the 0.1% PM2 threshold. Also absent from gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 0/251
  • 472 alleles (AF=0.0).
  • gnomAD v4.1: 2/1
  • 614
  • 256 alleles (AF=1.24×10⁻⁶)
  • 0 homozygotes.
  • gnomAD-Canada: absent.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest a benign effect: REVEL score 0.117 (below all pathogenic thresholds), BayesDel score −0.262 (benign direction), and SpliceAI max delta 0.05 (no predicted splice impact). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.117 (well below 0.29–0.5 pathogenic range).
  • BayesDel: −0.262 (negative score indicates benign).
  • SpliceAI: max delta 0.05 (no splicing alteration predicted).
Sources
revelbayesdelspliceai ↗

Not met · 4 · evaluated, threshold not reached

PM1 Not located in a statistically significant mutational hotspot. No HCI prior domain data available for H3C2. Details ▾Hide ▴
Evidence considered
  • Hotspot analysis: residue not significant
  • exact variant not listed in cancer hotspots. No HCI prior functional domain data for H3C2.
Still missing
  • H3C2 not covered by HCI prior
  • no VCEP-defined mutational hotspots.
PP3 Multiple computational tools do not support a deleterious effect: REVEL 0.117 (below typical pathogenic threshold of 0.29–0.5), BayesDel −0.262 (benign direction), and SpliceAI max delta 0.05 (no predicted splice impact). Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.117.
  • BayesDel score: −0.262.
  • SpliceAI max delta: 0.05
  • no significant splice prediction.
  • No HCI prior available.
Sources
revelbayesdelspliceai ↗
BA1 Allele frequency of 1.24×10⁻⁶ in gnomAD v4.1 is far below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=1.24×10⁻⁶
  • well below 1%.
Sources
gnomad_v4 ↗
BS1 Allele frequency of 1.24×10⁻⁶ in gnomAD v4.1 is far below the 0.3% BS1 threshold. Variant is absent from gnomAD v2.1. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=1.24×10⁻⁶
  • well below 0.3%
  • gnomAD v2.1 AF=0.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 16 · no assessment recorded

PS1 No prior pathogenic classification of this specific variant exists at this amino acid position from a reputable source. Variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no expert panel classification available.
Still missing
  • No prior classification of NM_003537.3:c.290G>C available for PS1 assessment.
Sources
clinvar ↗
PS2 No de novo data available for this variant. Details ▾Hide ▴
Still missing
  • No de novo reports identified for NM_003537.3:c.290G>C.
PS3 No well-established in vitro or in vivo functional studies identified for this specific variant. OncoKB found no variant-specific curated functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional evidence curated.
Still missing
  • No functional studies identified for NM_003537.3:c.290G>C (p.Cys97Ser).
Sources
oncokb ↗
PS4 Variant absent from ClinVar. No case-control, cohort, or clinical prevalence data available. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar with 0 submitters.
Still missing
  • No clinical observations or case-control data for NM_003537.3:c.290G>C.
Sources
clinvar ↗
PM6 No de novo reports identified for this variant. Details ▾Hide ▴
Still missing
  • No de novo observation of NM_003537.3:c.290G>C.
PP1 No segregation data available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data for NM_003537.3:c.290G>C.
PP2 H3C2 lacks established ClinGen gene-disease validity with missense as a common pathogenic mechanism. No CSPEC/VCEP framework available for PP2 applicability assessment. Details ▾Hide ▴
Evidence considered
  • No CSPEC/VCEP found for H3C2
  • no established gene-disease validity with defined missense constraint.
Still missing
  • No ClinGen gene-disease validity curation for H3C2 in germline context.
PP4 No specific phenotype or family history data available for this variant. Details ▾Hide ▴
Still missing
  • No clinical phenotype data associated with NM_003537.3:c.290G>C.
PP5 Variant absent from ClinVar. No expert panel classification or reputable source classification available. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • 0 submitters.
Still missing
  • No expert panel or reputable source classification.
Sources
clinvar ↗
BS2 Two heterozygous observations in gnomAD v4.1 (0 homozygotes) without established fully penetrant disease mechanism for H3C2. Insufficient to assess under BS2 in a generic ACMG framework. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 2 heterozygous observations
  • 0 homozygotes.
Still missing
  • No established penetrance data for H3C2 germline variants
  • 2 gnomAD observations cannot be assessed as healthy adult carriers without disease context.
Sources
gnomad_v4 ↗
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect for this variant. Details ▾Hide ▴
Still missing
  • No functional studies of NM_003537.3:c.290G>C demonstrating benign effect.
BS4 No segregation data showing lack of cosegregation with disease. Details ▾Hide ▴
Still missing
  • No family segregation data for NM_003537.3:c.290G>C.
BP2 No observation of this variant in trans with a known pathogenic variant. Details ▾Hide ▴
Still missing
  • No phase data
  • no observation in trans with a pathogenic H3C2 variant.
BP5 No case with an alternate molecular basis for disease identified. Details ▾Hide ▴
Still missing
  • No data on alternate molecular diagnoses in carriers of this variant.
BP6 No reputable source classifies this variant as benign. Variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar.
Still missing
  • No benign classification from a reputable source.
Sources
clinvar ↗
PS5 Variant absent from ClinVar. No established pathogenic variant at the same residue to serve as a comparator for PS5. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar.
Still missing
  • No ClinVar entries for this variant.
Sources
clinvar ↗
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Cys97Ser). Does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Variant is a substitution resulting in missense change (Cys97Ser)
  • variant_bucket is 'other'
  • apply_generic_pvs1_framework is false.
Sources
pvs1_generic_framework ↗
PM3 N/ANo phase-confirmed observation in trans with a pathogenic variant. No CSPEC/VCEP framework available for H3C2. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions and stop-loss variants; NM_003537.3:c.290G>C is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo confirmed pathogenic comparator variants at the same residue (Cys97) identified. PM5 candidate harvesting returned zero candidates. Details ▾Hide ▴
Evidence considered
  • PM5 candidate harvesting: 0 same-residue candidates found
  • recommendation level not_applicable.
Sources
pm5_candidates
BP1 N/AH3C2 has no established disease mechanism limited exclusively to truncating variants. BP1 applies only when missense variants occur in genes where only truncating variants cause disease. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_003537.3:c.290G>C is a missense variant (p.Cys97Ser), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing effect. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • not synonymous.

Identifiers

Gene
H3C2
Transcript
NM_003537.3
Coding (HGVS c.)
NM_003537.3:c.290G>C
Protein (HGVS p.)
NP_003528.1:p.(Cys97Ser)
GRCh38
chr6:26031771 C>G
GRCh37
chr6:26031999 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…
gnomAD v4.1 2 / 1,614,256 alleles AF 1.24e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1 0 / 251,472 alleles AF 0 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.2e-06 · 2 / 1,614,256 alleles · 0 hom · FAF 2.8e-07
European (non-Finnish)2 / 1,180,044 1.7e-06
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.

gnomAD v2.1

AF 0 · 0 / 251,472 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.23896e-06; MAF= 0.00012%, 2/1614256 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69485e-06; MAF= 0.00017%, 2/1180044 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251472 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16256 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -81 bp
0.010
SpliceAI acceptor gainat +31 bp
0.010
SpliceAI donor lossat +77 bp
0.050
SpliceAI donor gainat -13 bp
0.020
Pangolin splice lossmagnitude shown
-0.030
Pangolin splice gain
0.090

Other predictors

REVEL
0.117
BayesDel
-0.262

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest a benign effect: REVEL score 0.117 (below all pathogenic thresholds), BayesDel score −0.262 (benign direction), and SpliceAI max delta 0.05 (no predicted splice impact). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.117 (well below 0.29–0.5 pathogenic range).
  • BayesDel: −0.262 (negative score indicates benign).
  • SpliceAI: max delta 0.05 (no splicing alteration predicted).
Sources
revelbayesdelspliceai ↗
PP3 Multiple computational tools do not support a deleterious effect: REVEL 0.117 (below typical pathogenic threshold of 0.29–0.5), BayesDel −0.262 (benign direction), and SpliceAI max delta 0.05 (no predicted splice impact). Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.117.
  • BayesDel score: −0.262.
  • SpliceAI max delta: 0.05
  • no significant splice prediction.
  • No HCI prior available.
Sources
revelbayesdelspliceai ↗
BP7 N/ANM_003537.3:c.290G>C is a missense variant (p.Cys97Ser), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing effect. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.117. BayesDel score = -0.262425.

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 2 / 1,614,256 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.050 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

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= 1.23896e-06; MAF= 0.00012%, 2/1614256 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69485e-06; MAF= 0.00017%, 2/1180044 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251472 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16256 alleles, homozygotes = 0).

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 = 0.05). REVEL score = 0.117. BayesDel score = -0.262425.

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.