Variant Transcripts

Connected Insights performs variant annotation and matches variants to the records in external knowledge bases and functional impact predictions based on a set of pre-selected default transcripts. Variant details, such as c.HGVS and p.HGVS labels and consequences, are also generated based on default transcripts.

In the current implementation, you can only change transcripts for specific variants.

View default transcripts as follows.

1. Add the Transcript column in the variant grid of the Variants page. The HGVS and Consequences columns provide variants c.HGVS and p.HGVS labels and consequences based on the default transcript. Selecting More in the Consequences column shows all consequences for the default transcript (left column) and all transcripts including the default one (right column).

2. Open the Biomarker Details page by selecting Interpret on the Overview or Variants tabs. The default transcript is provided in the top-right corner.

3. Click the transcript button to view a list of transcripts that the variant impacts. A ☆ represents the default transcript, while a C represents the canonical transcript.

   1. A searchable dropdown shows all genes for transcripts that the variant overlaps. Select a gene symbol to filter the transcripts.

Default Transcript Selection

In Connected Insights, the following rules determine the default transcript:

1. If there are preferred transcripts annotated for the given report, limit to the list of preferred transcripts for a given variant. If there are no preferred transcripts for the given variant, skip this step.

2. When present, limit to the collection of transcripts for a given variant that have assertions from any source. This step prioritizes transcripts by highest assertion actionability, then by the most specific assertion level.

3. Limit to the collection of transcripts for a given variant that are the highest tier by consequence based on the variant category.

4. If canonical transcripts are present, limit to canonical transcripts.

5. Limit to the genes in the key genes configuration for the case disease.

6. When present, limit to the genes that have the highest role classification from Cancer Gene Census (Oncogene > Fusion > TSG).

7. Select the gene that is first alphabetically.

8. If RefSeq and Ensembl transcripts are present, limit to RefSeq transcripts.

9. If there are multiple transcripts remaining, select the first transcript alphabetically.

Assertions include the following levels:

• Nucleotide

• DNA

• Amino Acid

• Codon

• Exon

• Exact Fusion

• Annotation Overlap

• Gene

• Partial Fusion

The following variant categories define consequence tiers:

Consequence Tiers that Define Default Transcripts Setup

VariantCategory	Consequence Tier 1	Consequence Tier 2	Consequence Tier 3	Consequence Tier 4	Consequence Tier 5	Consequence Tier 6
Small Variant	• Gain of Function • Loss of Function	• Start Loss •Stop Gained • Stop Loss • Feature Truncation • Frame shift Variant • Splice Donor Variant • Splice Acceptor Variant	• Incomplete Terminal Codon • Feature Elongation • Splice Region Variant • Inframe Deletion • Inframe Insertion • Missense Variant • Protein Altering Variant • Coding Sequence Variant	• Intron Variant • 5' UTR Variant • 3' UTRVariant • Noncoding Transcript Exon Variant • Noncoding Transcript Variant • Synonymous Variant •Start Retained Variant • Stop Retained Variant •NMD Transcript Variant	• Upstream Gene Variant • Downstream Gene Variant • Mature miRNA Variant • Regulatory Region Ablation • Regulatory Region Amplification • Regulatory Region Variation •Any other undefined transcript consequences
Copy NumberVariant (CNV)	• Gain of Function • Loss of Function	• Copy Number Decrease • Loss of Heterozygosity	• Copy Number Increase • Copy Number Change	• Transcript Ablation • Feature Truncation • Feature Elongation	• Transcript Amplification •Transcript Variant • 5' Duplicated Transcript • 3' Duplicated Transcript	Any other undefined transcript consequences
Structural Variant or RNAFusion Variant	• Gain of Function • Loss of Function	• Unidirectional Gene Fusion	• Bidirectional Gene Fusion • Gene Fusion	• Transcript Ablation • Feature Truncation • Feature Elongation	• Transcript Amplification •Transcript Variant • 5' Duplicated Transcript • 3' Duplicated Transcript	Any other undefined transcript consequences
RNA Splice Variant	•Gain of Function •Loss of Function	Exon Loss Variant	Any other undefined transcript consequences

Changing Transcripts

In the current version of Connected Insights, users can only change transcripts for specific variants. The transcripts can be viewed and updated in the top-right corner of the Biomarker Details page for a specific variant. Changing transcripts updates the information for this variant in the variant grid and in the Biomarker Details page content. These updates include assertions in the following sections that have transcript-specific content:

• My Knowledge Base

• Other Knowledge Bases

• Clinical Trials

• Computer Predictors