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EZH2c.1852-9A>CLikely benign
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Variant interpretation report

EZH2 c.1852-9A>C, p.?

NM_004456.4:c.1852-9A>C NP_004447.2:p.? View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About EZH2

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: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is present in gnomAD at very low frequency (v2.1: AF=4.46e-05, 11/246,568 alleles; v4.1: AF=4.54e-05, 73/1,608,258 alleles; grpmax FAF=5.41e-05). The allele frequency is well below the 0.1% threshold for PM2 in non-VCEP adjudication.

Benign criteria applied · 2
BP4Supporting
BP4 · supporting

SpliceAI predicts no significant splice impact for this intronic variant (max delta score = 0.02), providing computational evidence that the variant does not disrupt normal splicing.

BP6Supporting
BP6 · supporting

This variant has been classified as Likely benign by Labcorp Genetics (formerly Invitae), a reputable clinical diagnostic laboratory, with ACMG criteria provided (ClinVar VariationID: 416828, SCV000562813).

Recorded classification: Likely benign

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 benign, BP6 supporting benign; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.

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
73 / 1,608,258 alleles

gnomAD v4.1: 73 / 1,608,258 alleles. Recorded AF 4.53907e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.46124e-05; MAF= 0.00446%, 11/246568 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.74003e-05; MAF= 0.00974%, 11/112936 alleles, homozygotes = 0); grpmax FAF= 5.414e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗
For specialists

Technical detail

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

27 criteria with recorded statuses: 3 met · 7 not met · 10 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_004456.4:c.1852-9A>C is an intronic variant in EZH2 located 9 bases upstream of exon 15, outside canonical splice consensus sites.

This variant is present in gnomAD at very low frequency (v2.1: 11/246,568 alleles, AF=0.0045%; v4.1: 73/1,608,258 alleles, AF=0.0045%) with no homozygotes observed. The allele frequency falls well below the 0.1% PM2 threshold (PM2_supporting).

SpliceAI predicts no significant splice impact (max delta score = 0.02), providing computational evidence that the variant does not disrupt normal splicing (BP4_supporting).

ClinVar classifies this variant as Likely benign (VariationID 416828) based on a submission from Labcorp Genetics with ACMG criteria provided. This constitutes supporting benign evidence from a reputable clinical source (BP6_supporting).

PVS1 is not applicable as the variant lies outside canonical splice ±1,2 consensus sites and does not fall into null-variant buckets per ClinGen SVI recommendations (PMC6185798). PM5, PP2, BP1, BP7 are not applicable as the variant is intronic, not missense or synonymous. BP3, PM3, PM4 were skipped per instruction as trivially not applicable.

Applying generic ACMG/AMP 2015 final classification combination rules: two supporting benign criteria (BP4, BP6) are met, which reaches the threshold for Likely benign. One supporting pathogenic criterion (PM2) is also met but does not alter the Likely benign classification under the standard combination rules.

Met · 3

PM2 SupportingThis variant is present in gnomAD at very low frequency (v2.1: AF=4.46e-05, 11/246,568 alleles; v4.1: AF=4.54e-05, 73/1,608,258 alleles; grpmax FAF=5.41e-05). The allele frequency is well below the 0.1% threshold for PM2 in non-VCEP adjudication. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF=0.0045% (11/246
  • 568)
  • v4.1 AF=0.0045% (73/1
  • 608
  • 258)
  • grpmax FAF=5.41e-05.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingSpliceAI predicts no significant splice impact for this intronic variant (max delta score = 0.02), providing computational evidence that the variant does not disrupt normal splicing. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.02
  • no predicted donor gain
  • donor loss
  • acceptor gain
  • or acceptor loss.
Sources
spliceai ↗
BP6 SupportingThis variant has been classified as Likely benign by Labcorp Genetics (formerly Invitae), a reputable clinical diagnostic laboratory, with ACMG criteria provided (ClinVar VariationID: 416828, SCV000562813). Details ▾Hide ▴
Evidence considered
  • ClinVar Likely benign classification from Labcorp Genetics (criteria provided
  • single submitter).
Sources
clinvar ↗

Not met · 7 · evaluated, threshold not reached

PS4 The variant has been observed in ClinVar as Likely benign (single submitter) and is present in gnomAD at low frequency (AF ~0.0045%). No case series or cohort study demonstrating enrichment in affected individuals was identified. Neither reviewed paper provides variant-specific case observations. Details ▾Hide ▴
Evidence considered
  • ClinVar Likely benign (1 submitter)
  • gnomAD presence at ~0.0045% in population controls.
Still missing
  • No case-control or cohort data comparing affected vs unaffected individuals.
Sources
clinvar ↗gnomad_v2 ↗gnomad_v4 ↗
PM1 The variant is not located in a well-established mutational hotspot or critical functional domain. Hotspot assessment found no significant residue-level clustering and the exact variant is not listed in known hotspot catalogs. Details ▾Hide ▴
Evidence considered
  • Residue not significant
  • exact variant not listed in hotspot databases.
PP3 SpliceAI predicts no significant splice impact (max delta score = 0.02). No other computational evidence (REVEL, BayesDel unavailable for intronic variant) supports a deleterious effect. Multiple lines of computational evidence do not support pathogenicity. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.02 (no predicted splice impact)
  • REVEL/BayesDel not applicable (intronic).
Sources
spliceai ↗
PP5 ClinVar classification for this variant is Likely benign (single submitter, Labcorp Genetics). No reputable source reports this variant as pathogenic. The GeneReviews article on EZH2-Related Overgrowth (PMID:23865096) does not mention this specific variant in available sources. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Likely benign
  • not pathogenic.
Sources
clinvar ↗
BA1 gnomAD allele frequency (0.0045%) is well below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF=0.0045%
  • v4.1 AF=0.0045%
  • far below 1% BA1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 gnomAD allele frequency (0.0045%) is well below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF=0.0045%
  • v4.1 AF=0.0045%
  • far below 0.3% BS1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional studies demonstrate no damaging effect of this variant on splicing or protein function. SpliceAI in silico prediction is addressed under BP4 and does not alone constitute BS3-level evidence. Details ▾Hide ▴
Evidence considered
  • No functional studies available for this variant.
Still missing
  • No experimental functional data (e.g.
  • splicing assays) available.

Not assessed · 10 · no assessment recorded

PS2 No de novo observation for NM_004456.4:c.1852-9A>C was identified in the reviewed literature or ClinVar submissions. Details ▾Hide ▴
Evidence considered
  • No de novo data available.
Still missing
  • De novo status not tested or reported in available sources.
PS3 No well-established functional studies evaluating the impact of this intronic variant on splicing or protein function were identified. Details ▾Hide ▴
Evidence considered
  • No functional data available.
Still missing
  • No functional assays (e.g.
  • RNA splicing analysis
  • minigene reporter) available for this variant.
PM6 No de novo observation (with or without maternity/paternity confirmation) for NM_004456.4:c.1852-9A>C was identified in the reviewed literature. Details ▾Hide ▴
Evidence considered
  • No de novo data available.
Still missing
  • De novo status not tested or reported in available sources.
PP1 No cosegregation data available for this variant in affected families. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • Cosegregation analysis not performed or not reported.
PP4 No detailed patient phenotype or family history data are available to assess specificity for EZH2-related Weaver syndrome. Details ▾Hide ▴
Evidence considered
  • No phenotype data available.
Still missing
  • Patient phenotype data not provided.
BS2 No documented observation of this variant in a healthy adult individual with full penetrance expected at an early age is available beyond population database frequencies. Details ▾Hide ▴
Evidence considered
  • No specific healthy adult observation data available.
Still missing
  • Healthy adult observation not specifically documented.
BS4 No segregation data available to assess lack of segregation with disease in affected families. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • Family segregation analysis not performed or not reported.
BP2 No observation of this variant in trans with a known pathogenic dominant EZH2 variant is available. Details ▾Hide ▴
Evidence considered
  • No trans observation data available.
Still missing
  • Observation in trans with pathogenic variant not documented.
BP5 No observation of this variant in an individual with an alternate molecular basis for Weaver syndrome or EZH2-related overgrowth is available. Details ▾Hide ▴
Evidence considered
  • No case with alternate molecular basis identified.
Still missing
  • No reported case where alternate molecular cause was found.
PS5 No reputable source has recently reported this variant as pathogenic with unavailable supporting evidence. Details ▾Hide ▴
Evidence considered
  • No qualifying PS5 source identified.
Still missing
  • No recent pathogenic assertion from a reputable source lacking accessible evidence.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AIntronic variant (c.1852-9A>C) located outside canonical splice donor/acceptor ±1,2 consensus sites. Does not fall into PVS1 null-variant buckets (nonsense, frameshift, or canonical splice) per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Intronic variant outside canonical splice consensus
  • pvs1_variant_assessment confirms variant_bucket='other'
  • apply_generic_pvs1_framework=false.
Sources
pvs1_generic_framework ↗
PS1 N/AIntronic variant produces no amino acid change; cannot compare to a pathogenic missense change at the same residue. Details ▾Hide ▴
Evidence considered
  • Intronic variant with no predicted protein consequence (NP_004447.2:p.?).
PM5 N/AIntronic variant; no missense residue to compare. pm5_candidates.json confirms no classic same-residue PM5 semantics applicable. Details ▾Hide ▴
Evidence considered
  • Intronic variant with no protein residue
  • PM5 mode=unknown.
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. NM_004456.4:c.1852-9A>C is an intronic variant, not a missense change. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • PP2 requires missense.
BP1 N/ABP1 applies to missense variants in genes where truncating variants are a known mechanism of disease. NM_004456.4:c.1852-9A>C is an intronic variant, not a missense change. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • BP1 requires missense.
BP3 N/ASkipped per instruction: trivially not_applicable. BP3 applies to in-frame deletions/insertions in repetitive regions; this is a single-nucleotide intronic substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous (silent) coding variants with no predicted splice impact. NM_004456.4:c.1852-9A>C is an intronic variant, not a synonymous coding change. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • BP7 requires synonymous coding change.

Identifiers

Gene
EZH2
Transcript
NM_004456.4
Coding (HGVS c.)
NM_004456.4:c.1852-9A>C
Protein (HGVS p.)
NP_004447.2:p.?
GRCh38
chr7:148811729 T>G
GRCh37
chr7:148508821 T>G
ClinVar
416828

Gene diagram

Every interpreted variant in EZH2, mapped onto the exon structure of NM_004456.4. Select a row to find it on the plot.

EZH2NM_004456.4
Fetching transcript structure from UCSC…
gnomAD v4.1 73 / 1,608,258 alleles AF 4.54e-05 · 0 homozygotes · FAF 4.79e-05
gnomAD v2.1 11 / 246,568 alleles AF 4.46e-05 · 0 homozygotes · FAF 5.41e-05
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 4.5e-05 · 73 / 1,608,258 alleles · 0 hom · FAF 4.8e-05
European (non-Finnish)70 / 1,178,228 5.9e-05
Remaining individuals2 / 62,414 3.2e-05
South Asian1 / 91,016 1.1e-05
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 4.5e-05 · 11 / 246,568 alleles · 0 hom · FAF 5.4e-05
European (non-Finnish)11 / 112,936 9.7e-05
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 4.53907e-05; MAF= 0.00454%, 73/1608258 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.94113e-05; MAF= 0.00594%, 70/1178228 alleles, homozygotes = 0); grpmax FAF= 4.788e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.46124e-05; MAF= 0.00446%, 11/246568 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.74003e-05; MAF= 0.00974%, 11/112936 alleles, homozygotes = 0); grpmax FAF= 5.414e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +339 bp
0.020
SpliceAI acceptor gainat -9 bp
0.000
SpliceAI donor lossat +221 bp
0.010
SpliceAI donor gainat +100 bp
0.010
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingSpliceAI predicts no significant splice impact for this intronic variant (max delta score = 0.02), providing computational evidence that the variant does not disrupt normal splicing. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.02
  • no predicted donor gain
  • donor loss
  • acceptor gain
  • or acceptor loss.
Sources
spliceai ↗
PP3 SpliceAI predicts no significant splice impact (max delta score = 0.02). No other computational evidence (REVEL, BayesDel unavailable for intronic variant) supports a deleterious effect. Multiple lines of computational evidence do not support pathogenicity. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.02 (no predicted splice impact)
  • REVEL/BayesDel not applicable (intronic).
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous (silent) coding variants with no predicted splice impact. NM_004456.4:c.1852-9A>C is an intronic variant, not a synonymous coding change. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • BP7 requires synonymous coding change.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • EZH2-Related Overgrowth.
    Adam MP et al. · 1993
    GeneReviews clinical summary on EZH2-Related Overgrowth (Weaver syndrome). Discusses EZH2 germline variants in the context of overgrowth and intellectual disability at the gene level. NM_004456.4:c.1852-9A>C was not identified in available sources.
    Does not name this variant
    PMID 23865096 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Methodology paper describing the Sherloc refinement of ACMG-AMP variant classification criteria. Reviews a general framework for variant classification without mention of specific EZH2 variants. NM_004456.4:c.1852-9A>C was not identified in this paper.
    Does not name this variant
    PMID 28492532 ↗
    Quoted passage
    We undertook an iterative process of refining the ACMG-AMP guidelines. We used the guidelines to classify more than 40,000 clinically observed variants, assessed the outcome, and refined the classification criteria to capture exceptions and edge cases.

    Abstract confirms general classification methodology focus.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 73 / 1,608,258 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar 1 Likely benign Open source ↗
COSMIC Captured COSMIC 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= 4.53907e-05; MAF= 0.00454%, 73/1608258 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.94113e-05; MAF= 0.00594%, 70/1178228 alleles, homozygotes = 0); grpmax FAF= 4.788e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.46124e-05; MAF= 0.00446%, 11/246568 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.74003e-05; MAF= 0.00974%, 11/112936 alleles, homozygotes = 0); grpmax FAF= 5.414e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 416828)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).