Emedgene
Illumina Connected Software
  • Get Started with Emedgene
    • Get started with Emedgene
    • How can Emedgene help you solve a case?
  • Emedgene analyze manual
    • Getting around the platform
      • Top navigation panel
      • Emedgene Applications menu
      • Dashboard
      • Settings
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      • Okta identity management
    • Managing data storage
      • Manage data storages
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      • Bring Your Own Bucket
      • Bring Your Own Key
    • Cases tab
      • Cases tab
      • Cases table
      • Case status
      • Browse and select cases
      • Case details
    • Creating a single case
      • Add a new case
      • Select sample type
      • Create a family tree
      • Family tree legend
      • Add a sample
      • Supported Variant callers
      • Adding patient info for the proband
      • Adding patient info for the non-proband samples
      • Secondary findings
      • Labeling a case
      • Gene list
      • Supported parental ethnicities
    • Creating multiple cases
      • Batch case upload from platform
      • CSV format requirements
      • Batch case upload via CLI
    • Reviewing a case
      • Individual case page
      • Individual case page: Top bar
      • Individual case page: Top bar
      • Candidates tab
      • Most Likely Candidates and Candidates
      • Genome Overview
      • Analysis tools tab
      • Variant table columns
      • Variant table
      • Variant search
      • Multiselection of variants and bulk actions (34.0+)
      • Download variants
      • Manually add variants to a delivered case
      • Filters/Presets panel
      • Filters
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      • Preset groups
      • Variant Type Filters
      • Variant Effect Filters
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      • Evidence page
      • Phenotypic match strength
      • Lab tab
      • Versions tab
      • Editing an existing case
      • Finalizing a case
      • Clinical Report
      • Reflex genetic testing
      • Variant zygosity notations
      • STR calling and interpretation
    • Variant page
      • Variant page
      • Variant page top bar
      • Variant tagging widget
      • Variant activity panel
      • Desktop apps panel
      • Clinical Significance section
      • Summary section
      • Quality section
      • Visualization section
      • Population Statistics section
      • Related Cases section
      • CNV overlap percentage
      • Evidence section
      • ACMG SNV Classification wizard
      • Logic behind ACMG classification of SNVs
      • ACMG CNV Classification wizard
      • Variant page sidebar (2.29+)
    • Variant visualization setup
      • Enabling visualization for a VCF case
      • Integration between emedgene and desktop IGV
      • Loading alignment files to your desktop IGV (32.0+)
    • Analyze Network
      • Analyze Network Setup
      • Network sharing configuration
      • Case subject consent for extended sharing
      • Public vs Private network
      • Create a network
      • Set network data sharing policy
      • Leave a network
      • Delete a network
    • Settings
      • My settings
      • Management
      • User Management
      • Network
      • Organization Settings (33.0+)
    • Integrations
      • API Beginner Guide
      • Advanced API Implementations
      • API Key Generation
      • BSSH Integration
      • ICA Integration
      • Webhook Integration
  • Emedgene Curate Manual
    • Curate overview
      • Curate overview
      • Emedgene Applications menu
      • Curate navigation panel
      • Genome assemblies supported by Curate
    • Curate Variants
      • Curate Variants overview
      • Curate Variant table
      • Curate Variant page
      • How to add a variant to Curate
      • Curate Variant annotations in the case
    • Curate Genes (2.28+)
      • Curate Genes overview
      • Curate Gene table
      • Curate Gene page
      • How to add a gene to Curate
    • Import Curate annotations to the case (30.0+)
      • Import Curate Variant annotations to the case (30.0+)
      • Import Curate Gene annotations to the case (30.0+)
  • Frequently Asked Questions
    • All FAQ
      • Which browser should I use with Emedgene?
      • Emedgene annotations and update frequency
      • How do I use developer tools to collect logs?
      • Can I analyze Illumina Complete Long Reads in Emedgene?
      • How do I prepare VCF files generated by DRAGEN MANTA to be used as input for Emedgene?
      • Source of gnomAD data for small variants on GRCh38
      • How are MNVs handled on the platform?
      • Support for gene lists with up to 10,000 genes
      • Genomic Regions by Case Type
      • How do I analyze mtDNA variants?
      • Can I use exome data for CNV detection?
      • How does joint calling work on Emedgene?
      • What is the required format for a BED file defining a kit?
      • Which reference genomes can I use?
      • How do I move between organizations?
      • How do I check the version of my environment?
      • "Failed to generate report". What should I do?
      • How do I prepare VCF files generated by Dragen STR (ExpansionHunter) to be used as input?
      • How does Emedgene Analyze prioritize transcripts?
      • How does Emedgene Analyze merge variants from different sources?
      • Performance issue troubleshooting
      • How does Emedgene calculate variant effect and severity ?
      • How to I prepare metrics files generated by DRAGEN to be used as input for Emedgene
      • How are timekeeping and log timestamps kept accurate and consistent?
  • Release Notes
    • Workbench & Pipeline Updates
      • New in Emedgene V37.0 (February 20, 2025)
        • V37 Patches
      • New in Emedgene V36.0 (October 8 2024)
        • V36 Patches
      • New in Emedgene V35.0 (May 22nd 2024)
        • V35 Patches
      • New in Emedgene V34.0 (January 28th 2024)
        • V34 Patches
      • New in Emedgene V33.0 (September 6th 2023)
        • V33 Patches
      • New in Emedgene V32.0 (June 8th 2023)
        • New pipeline 32 (June 8th 2023)
        • V32 Patches
      • More release notes
        • New in emedgene 31 (March 1st 2023)
        • New in emedgene 30 (January 8th 2023)
        • New in emedgene 2.29 (August 25 2022)
        • New pipeline 5.29 (May 1st 2022)
        • New in emedgene 2.28 (May 1 2022)
        • New in emedgene 2.27 (March 7, 2022)
        • New in emedgene 2.26 (Dec 14, 2021)
        • New in emedgene 2.24-2.25 (Aug 11, 2021)
        • New in emedgene 2.23 (Jun 15, 2021)
        • New in emedgene 2.19-2.22 (Apr 8, 2021)
        • New in emedgene 2.16-2.19 (Dec 7, 2020)
        • New in emedgene 2.12-2.16 (Oct 18, 2020)
    • Knowledgebase Updates
      • 2025
        • Variant Databases (March 30th 2025)
        • Zoidberg 77 (March 17th 2025)
        • Zoidberg 76 (February 3rd 2025)
        • Zoidberg 75 (January 6th 2025)
      • 2024
        • Variant Databases (December 8th 2024)
        • Zoidberg 74 (December 2nd 2024)
        • Zoidberg 73 (October 21th 2024)
        • Variant Databases (September 22nd 2024)
        • Zoidberg 72 (September 10th 2024)
        • Variant Databases (July 21st 2024)
        • Zoidberg 71 (July 24th 2024)
        • Zoidberg 70 (June 3rd 2024)
        • Zoidberg 69 (April 19th 2024)
        • Variant Databases (April 9th 2024)
        • Zoidberg 68 (March 18th 2024)
        • Variant Databases (February 5th 2024)
        • Zoidberg 67 (January 28th 2024)
        • Variant Databases (January 5th 2024)
      • 2023
        • Zoidberg 66 (December 24th 2023)
        • Variant Databases (December 3rd 2023)
        • Zoidberg 65 (November 21th 2023)
        • Variant Databases (November 5th 2023)
        • Zoidberg 64 (October 24th 2023)
        • Variant Databases (October 8th 2023)
        • Zoidberg 63 (September 18th 2023)
        • Variant Databases (September 5th 2023)
        • Zoidberg 62 (August 23th 2023)
        • Zoidberg 61 (August 16th 2023)
        • Variant Databases (August 6th 2023)
        • Zoidberg 60 (July 30th 2023)
        • Variant Databases (July 2nd 2023)
        • Zoidberg 59 (June 18th 2023)
        • Variant Databases (June 4th 2023)
          • Variant Databases (May 7th 2023)
        • Zoidberg 58 (May 21th 2023)
        • Zoidberg 57 (April 16th 2023)
        • Variant Databases (April 2nd 2023)
        • Zoidberg 56 (March 19th 2023)
        • Variant Databases (March 11th 2023)
        • Zoidberg 55 (February 19th 2023)
        • Zoidberg 54 (January 16th 2023)
    • Change log
      • Change log pipeline v34
      • Change log pipeline 31
      • Change log workbench 31
      • Change log pipeline 30
      • Change log workbench 30
      • Change log workbench 2.29
      • Change log pipeline 5.29
      • Change log workbench 2.28
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  • This tab is comprised of five different blocks:
  • 1. Variant Info
  • 2. In silico Predictions
  • 3. Gene Metrics
  • 4. Gene's related diseases
  • 5. Clinical significance

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  1. Emedgene analyze manual
  2. Variant page

Clinical Significance section

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Last updated 1 month ago

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The Clinical Significance section summarizes essential variant-level and gene-level information and indicates the gene's associated diseases.

This tab is comprised of five different blocks:

1. Variant Info

  1. Variant type,

  2. Main effect,

  3. Zygosity in each sequenced family member,

  4. Gene symbol and HGVS descriptions on coding DNA and protein levels. The transcript is marked:

    • with a tick - if it is canonical,

  1. Exon number and the total number of exons in the transcript chosen,

  2. Links to resources, such as UCSC genome browser, GeneCards, PubMed, WikiGenes,

  3. dbSNP ID and link (Note: SNV/Indel variants only),

  4. SV Type: DEL/DUP (Note: CNVs only),

  5. SV Length (Note: CNVs only),

  6. Link to DECIPHER (Note: CNVs only).

2. In silico Predictions

Standalone scores for Pathogenicity (Missense) Prediction, Conservation, and Splicing Prediction. These are the summarized indicators computed by our proprietary algorithm based on the in silico prediction tools' output. Click on the dropdown icon next to the score to see the individual scores.

Currently available in silico predictions per variant type:

SNV
Indel
mtDNA (SNV/indel)

Pathogenicity (Missense) Prediction

+ Polyphen2 HDIV Polyphen2 HVAR SIFT MutationTaster LRT DANN REVEL PrimateAI-3D (34.0+)

-

+ APOGEE MitoTIP

Conservation

+ SiPhy 29 Mammals GERP RS phastCons 100 vertebrate

+

GERP RS

-

Splicing Prediction

+ dbscSNV-RF dbscSNV-Ada SpliceAI DS AG SpliceAI DS AL SpliceAI DS DG SpliceAI DS DL

-

-

Note: variants of types CNV, SV and STR are not annotated with in silico predictions.

3. Gene Metrics

from ExAC and gnomAD that resemble clinically relevant gene properties:

1. p(LoF intolerant)

pLI = p(LoF intolerant) is a probability of being loss-of-function intolerant to heterozygous and homozygous LoF variants.

Scale:

  • 🔴 pLI ≥ 0.9: extremely LoF intolerant,

  • 🟠 pLI > 0.1 & < 0.9: intermediate value,

  • 🟢 pLI ≤ 0.1: LoF tolerant.

2. Z missense

The Z missense score indicates intolerance to missense variants based on the deviation of observed missense variants versus the expected number.

Scale:

  • 🔴 Z missense ≥ 3: missense intolerant,

  • 🟠 Z missense > 2.5 & < 3: intermediate value,

  • 🟢 Z missense ≤ 2.5: missense tolerant.

3. p(REC)

p(REC) is a probability of being intolerant to homozygous, but not heterozygous LoF.

Scale:

  • 🔴 p(REC) ≥ 0.8: Hom LoF intolerant,

  • 🟠 p(REC) > 0.2 & < 0.8: intermediate value,

  • 🟢 p(REC) ≤ 0.2: Hom LoF tolerant.

4. RVIS ratio

RVIS = Residual Variation Intolerance Score is indicative of a gene's intolerance to functional variation based on comparing the overall number of observed variants in a gene to the observed common functional variants.

Scale:

  • 🔴 RVIS ≤ 30: functional variation intolerant,

  • 🟠 RVIS > 30 & < 50: intermediate value,

  • 🟢 RVIS ≥ 50: functional variation tolerant.

5. pLoF o/e

O/E Score is the ratio of the observed/expected number of LoF variants. It is a continuous measure of gene tolerance to LoF variation that incorporates a 90% confidence interval. The closer the O/E is to zero, the more likely the gene is LoF-constrained. If a hard threshold is needed for the interpretation of Mendelian disease cases, use the upper bound of the O/E confidence interval < 0.35.

Note: Gene Metrics are not available for CNVs or mtDNA variants.

4. Gene's related diseases

as reported in OMIM, ORPHANET, CGD, ClinVar, and academic papers included in the Emedgene's knowledge graph. Each of the entries is provided with an inheritance mode icon and a link to the source.

5. Clinical significance

highlights previous pathogenicity classifications of the variant under review:

  • Manually Classified indicates if the variant has been previously classified in any of the organization's cases by any user.

  • ClinVar provides a list of ClinVar submissions for the selected variant.

  • ClinGen Regions (only for CNVs) indicates whether a variant overlaps the established dosage-sensitive region defined by ClinGen.

  • Custom database shows a variant class from the variant database(s) curated by your organization. We can easily implement an organization's curated database of classified SNV or CNV variants to facilitate the case review.

with a Curate logo - if it has been selected in your database.

You may change the reference transcript by selecting one from the dropdown menu, or adding one not listed. For certain variants, such as upstream or downstream gene variants, HGVS descriptions may not be available. In these cases, you have the option to manually input coding change information. The notation should adhere to the format: GENE,NM_123456:c.-123N>N (no spaces are allowed). Once added, this information becomes available for the .\

Networks Classified indicates if the variant has been previously classified by the partnering organizations in your .

Caution: Please be aware that as of 32.0 there might be instances where the Variant page > Clinical significance > Networks classified section appears erroneously empty. However, you can still rely on the Variant page > , which will continue to display relevant information as intended. Please utilize the Variant page > Related cases section while the fix is being implemented.

indicates if the variant has been previously classified in your Curate variant database.

MITOMAP shows a variant's status in . By clicking on the MITOMAP interactive link, you will be taken to .

Curate
report
network
Related cases
Curate
MITOMAP
MITOMAP: Reported Mitochondrial DNA Base Substitution Diseases: Coding and Control Region Point Mutations