Dosage sensitivity scores

Dosage sensitivity (DS) scores are Log-odds (LOD) scores as described in Huang et al. 2010 (PMID: 20976243), based on the predicted haploinsufficiency of individual genes within the deletion or duplication. This metric is based on the ratio of the probability that none of the genes within the copy-number variant is dosage-sensitive and the probability that at least one of the affected* genes is dosage-sensitive. A high positive score indicates that the copy-number variant is more likely to be pathogenic than a copy-number variant with a lower positive score, or a negative score.

* A gene is only considered to have been affected by a CNV if all protein-coding transcripts in that gene intersect with the CNV.

The dosage sensitivity scores calculated here are based on more recent, improved, haploinsufficiency predictions (version 3), generated since the original publication.

Dosage sensitivity sampling probability

The dosage sensitivity sampling probability is an estimate of the proportion of the general population that carry a rare (observed in fewer than 1% of individuals) deletion/duplication with a dosage sensitivity score as severe or more severe than for the copy-number variant being assessed. This metric is estimated separately for deletions and duplications, using 5,919 GWAS controls from the WTCCC.

The dosage sensitivity sampling probability is binned into three categories:

> 5% A similarly damaging copy-number variant would be expected to be observed in greater than 5% of apparently healthy individuals
1% - 5% A similarly damaging copy-number variant would be expected to be observed in 1% to 5% of apparently healthy individuals
< 1% A similarly damaging copy-number variant would be expected to be observed in fewer than 1% of apparently healthy individuals

Please note that this sampling probability is not an estimate of the statistical confidence that a variant is pathogenic, but is given to provide a sense of the frequency with which a similarly damaging copy-number variant might be observed in an apparently healthy individual.