UCSC Genome Browser · Tutorial 4
Clinical case studies
Real diagnostic variants, worked live on the Browser
Coding · splicing · non-coding · structural & repeat · genome.ucsc.edu
How these case studies work
- Each case is a real diagnostic variant saved as a live UCSC session — open it and follow along.
- They are grouped by variant class: coding, splicing, non-coding/regulatory, and structural/repeat.
- The recurring move: pick the right Recommended Track Set, then read the evidence off the stacked tracks.
- Cases contributed by clinical collaborators (credited per slide); sessions are public.
Builds on Tutorial 3 Tutorial 3 introduced the tracks and Recommended Track Sets; here we put them to work on one variant after another.
Coding variants
read the call — then check the transcript
MECP2 — Rett syndrome
NM_001110792.2(MECP2):c.538C>T p.Arg180Ter (R168X) chrX
- X-linked neurodevelopmental disorder; a classic loss-of-function nonsense variant.
- You can paste the HGVS expression straight into the position box and press Enter.
Read it off the set Load the Clinical SNVs Recommended Track Set: ClinVar, HGMD and LOVD stack the pathogenic evidence at the codon.
Try it, ▶ open the session Paste the HGVS, then open Recommended Track Sets → Clinical SNVs.
Session: s/Max/rett
MAP2K2 — a small missense
NM_030662.4(MAP2K2):c.401A>G p.Tyr134Cys
- A RASopathy-gene missense change — the everyday coding question.
- The SNV Recommended Track Set is on display here.
Lines of evidence ClinVar submitted interpretations & evidence, plus Varaico literature annotations for Y134C, sit together in one view.
Try it, ▶ open the session Read the ClinVar interpretations and the Varaico annotation for Y134C.
Example session (variant via Marina Di Stefano, Broad Institute)
Read the annotation carefully
when a coding call isn't what it seems
TCF4 — but do you trust this exon?
p.Ser504Ter chr18:55,234,435G>T ENST00000635822.2
- Gene implicated in a syndromic intellectual disability; this looks like a stop-gain.
- But the exon is coding only in one transcript, and it is not conserved across vertebrates.
The catch If the exon is not a real coding region, the “nonsense” call collapses — the variant is most likely benign. Always check the transcript and conservation.
Try it, ▶ open the session Compare transcripts; read the 100-vertebrate conservation over this exon.
Case: Irina Giurgea, Hôpital Trousseau
Splicing
synonymous and deep-intronic variants that still break splicing
IGHMBP2 — a new splice site deep in an intron
NM_002180(IGHMBP2):c.712-610A>G hg38 chr11:68,914,208
- A variant deep in an intron, far from any coding exon — easy to dismiss.
- But it can create a new splice site.
Scan the predictors The Splicing Impact / SpliceAI track flags the gain; SpliceVarDB and a PubTator hit corroborate it.
Try it, ▶ open the session Turn on Splicing Impact; inspect the SpliceAI delta scores at the variant.
Session: s/Max/ighmbp2.712 · PMID 33189025
KCTD7 — a synonymous variant that isn't silent
KCTD7:c.456G>A p.Val152Val exon 3
- A synonymous change — no amino-acid change, so it looks harmless.
- But it disrupts splicing.
Synonymous ≠ silent The Splicing Impact track shows the effect; the variant is in the LOVD of a 2019 paper from the same lab.
Try it, ▶ open the session Check the splicing predictions over this synonymous position.
Session: s/Max/kctd7.456GA · PMC10506157
Non-coding & regulatory
enhancers, promoters and RNA genes
POU1F1 — a deletion upstream of the gene
8.7 kb deletion, ~3 kb upstream hg38 chr3:87,279,612-87,288,322
- Homozygous deletion upstream of POU1F1, a pituitary transcription factor (pituitary hormone deficiency).
- No coding sequence is touched — the evidence is regulatory.
Read the regulation The deletion removes an ENCODE cCRE with a distal-enhancer signature; conservation and GTEx (pituitary +++) support its role.
Try it, ▶ open the session Turn on ENCODE cCREs, 100-vertebrate conservation, and GTEx over the deleted region.
Case: Amselem & Legendre labs, Hôpital Trousseau
SHH / ZRS — a limb enhancer in an intron of LMBR1
Patient chr7:156,791,472C>T intron 5 of LMBR1 (the ZRS)
- The ZRS is a classic long-range enhancer of SHH; variants in it cause limb malformations.
- In snakes, a 17 bp ZRS deletion contributed to limb loss (Kvon et al.).
Motif in an enhancer BLAT the snake sequence and Short Match the ETS1 motif; the patient variant sits in a conserved ETS motif inside a distal-enhancer cCRE, with other OMIM-allele patients nearby.
Try it, ▶ open the session Use BLAT / Short Match for the ETS motif; read the cCRE, conservation and OMIM alleles.
Cases: Wieczorek et al. 2009; snake example: Kvon et al.
RNU4-2 — a variant in a non-coding RNA gene
hg38 chr12:120,291,858 C>T RNU4-2 (NR_003137.3):n.46G>A
- RNU4-2 encodes the U4 spliceosomal snRNA — a non-coding RNA gene, not a protein.
- Recently (2024) shown to cause one of the most common monogenic neurodevelopmental disorders (ReNU syndrome).
No protein here There is no coding consequence to read; you reason from the RNA gene itself and the recent literature.
Try it, ▶ open the session View the variant within the RNU4-2 gene body; a second hotspot sits at n.129G>A.
Case: Jon Bernstein · medRxiv 2025
Structural & repeat
CNVs and repeat expansions
A 2.22 Mb duplication on chromosome 22
chr22:g.18,895,798-21,111,753dup GRCh38 2.22 Mb
- A large copy-number gain at 22q11.2 — a different interpretation problem from SNVs.
- Load the CNV Recommended Track Set.
CNV-specific evidence ClinGen Dosage (triplosensitivity), ClinVar CNVs, DECIPHER and PanelApp CNV regions — each filterable.
Try it, ▶ open the session Load the CNV RTS; compare the duplication against ClinGen Dosage and DECIPHER.
Example session
FGF14 — a GAA repeat expansion
FGF14 intron 1 hg38 chr13:102,161,567 ~270-300 GAA repeats
- Late-onset cerebellar ataxia (SCA27B) caused by an intronic repeat expansion — not an SNV or CNV.
- A distinct class of variant with its own resources.
A third variant class View the intron-1 GAA locus in the Browser, then cross-check dedicated tandem-repeat resources (WebSTR, TRatlas).
Try it, ▶ open the session Navigate to the intron-1 repeat; compare against the tandem-repeat tracks/resources.
Session: s/Max/fgf14
More cases
a gallery of de novo neurodevelopmental variants
More cases: de novo neurodevelopmental variants
A gallery of further worked cases (GSS series) — each opens as a live session:
- LRRC8A c.730T>C p.Phe244Leu — multisystem disorder, de novo heterozygous. session
- KPNA4 c.557G>A p.Gly186Asp chr3:160,526,107C>T — seizures, developmental delay, autism. session
- ERCC8 c.550+2T>C splice + a complex maternal SV — compound heterozygous, Cockayne-spectrum. session
- RNU4ATAC n.12C>T + n.120T>G — minor-spliceosome snRNA, compound heterozygous, multisystem.
Same recipe Different genes and mechanisms, one workflow: open the session, load the right track set, read the evidence.
What these cases show
- Coding variants can be read almost off the tracks — but always check the transcript and conservation (TCF4).
- Synonymous and deep-intronic variants can still break splicing — scan the splicing predictors.
- Non-coding variants are interpreted from regulatory context: cCREs, conservation, expression, TF motifs.
- CNVs and repeat expansions are their own classes, each with dedicated tracks and resources.
The habit Turn every variant into a set of questions, then let the right track answer each one.
Thank you!
Questions? · genome@soe.ucsc.edu
UCSC Genome Browser · genome.ucsc.edu
