Table 2. Summary of the five TCF12 variants.
| Proband | cDNAa | Exon/intron | Amino acid | Domain | Cosegregates or de novo and penetrance | Novel or reported | Amino acid conserved | Mutation taster | Polyphen | SIFT | Splicing prediction toolsb or minigene splicing assay |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | c.596dup | Ex 9 | p.(Asn200Lysfs*4) | — | ND | Novel | — | — | — | — | — |
| 2 | c.842C>G | Ex 11 | p.(Ser281*) | — | De novo | Ref. 9 | Highly conserved | — | — | — | — |
| 3 | c.826-2A>G | Int 10 | — | Activation domain 2 | De novo | Novel | — | — | — | — | Predicted to ablate splicing acceptor site. Minigene assay revealed the creation of two aberrant splicing products (Figure 2). |
| 4 | c.1144C>T | Ex 14 | p.(Gln382*) | Activation domain 2 | Cosegregation and incomplete penetrance (unaffected cousin) | Novel | Highly conserved | — | — | — | — |
| 5 | c.1520T>Gc | Ex 17 | p.(Leu507Arg) | Activation domain 2 | Incomplete penetrance (unaffected father) | rs36060670 (EVS:11/2184 European Americans) | Moderately conserved | 1.0 Dis | 0.4 Benign | 0.01 Del | — |
Abbreviations: EVS, Exon variant Server; ND, not determined.
The predictive pathogenicity is indicated for the novel alterations.
a
TCF12 transcript NM_207037.1.
b
Five splicing tools available in Alamut V2.0, SpliceSite Finder-like, MaxEntScan, NNSPlice, GeneSplicer and Human Splicing Factor. Patients and variants have been submitted to the gene variant database at www.LOVD.nl/CAV3.
c
Pathogenicity uncertain until functional analysis is undertaken. Predictive pathogenicity tools: PolyPhen: Benign—predicted to be non-disease causing. SIFT: Del—deleterious. MutationTaster: Dis—disease causing.