Table 6.
Assessment of variant frequency in the general population for curated variant classification. Variants in some common genetic disorders with their known incidences for dominant (Kabuki syndrome and CHARGE syndrome), X linked diseases (Rett syndrome), and carrier frequencies for recessive disorders (Cystic Fibrosis, Phenylketonuria (PKU), Medium Co-Acyl Dehydrogenase Deficiency (MCADD), Autosomal Recessive Polycystic Kidney Disease (ARPKD), GJB2 associated hearing loss, and Hemochromatosis) are shown in the table. Some variants found in the ESP-GO database in these genes are listed with the variant classifications based on evidence and concordance with allele frequencies in African American (AA) and European American (EA) subpopulations. Variants that have an allele frequency greater than expected for the disorder in at least one subpopulation (AA or EA) of individuals not known to have the disorder can be considered to have strong evidence of benign impact (BS1). Variants known to be pathogenic for dominant disorders should have allele frequencies in the general population below the population disease incidence or and pathogenic variants for recessive disorders should have heterozygous frequencies consistent with their disease incidence. The allele frequencies shown in the table for certain variants are lower for certain benign and higher for certain pathogenic variants than the disease incidence/carrier frequency; therefore other data would be required to classify these variants. Variants represented in the concordance column are designated as partial when a subpopulation frequency does not conform as above or when concordance is not achieved. Variants are designated as having partial concordance when a single subpopulation frequency is inconsistent with the classification.
| Disease | Gene | Inheritance | Population | Incidence | Carrier Frequency |
Common Mutation | Variant Classification | ESP6500 AA MAF |
ESP6500 EA MAF |
ESP6500 All MAF |
Concordance | Evidence to support classification |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cystic fibrosis | CFTR | AR | Caucasian | 0.031% | 3.6% | p.F508del | Ex24:p.F508del (Pathogenic) | n/a | n/a | n/a | n/a | Multiple publications (note variant not available in EVS) |
| Ex11:c.1523T>G / p.F508C (Benign) | 0.070% | 0.150% | 0.120% | No | Kobayashi (1990) Am J Hum Genet 47, 61 | |||||||
| Ex23:c.3870A>G / p.(=) (Benign) | 15.090% | 2.970% | 7.070% | Partial | AA MAF | |||||||
| 5' UTR:c.-8G>C (Benign) | 1.160% | 5.550% | 4.060% | Partial | EA MAF | |||||||
| IVS6:c.743+40A>G (Benign) | 0.700% | 5.190% | 3.670% | Partial | EA MAF | |||||||
| Phenylketoneuria | PAH | AR | North European | 0.010% | 2.0% | Ex12:c.1242C>T / p.(=) (Benign) | 0.360% | 1.310% | 0.990% | No | PAH database | |
| Ex12:c.1278T>C / p.(=) (Benign) | 13.550% | 0.090% | 4.650% | Partial | AA MAF | |||||||
| IVS12:c.1316-35C>T (Benign) | 0.320% | 2.630% | 1.850% | Partial | EA MAF | |||||||
| Ex9:c.963C>T / p.(=) (Benign) | 5.170% | 0.000% | 1.750% | Partial | AA MAF | |||||||
| MCADD | ACADM | AR | Not specific | 0.006% | 1.5% | p.K329E aka p.K304E | Ex7:c.489T>G / p.(=) (Benign) | 7.010% | 0.050% | 2.410% | Partial | AA MAF |
| ARPKD | PKHD1 | AR | Not specific | 0.005% | 1.4% | IVS20:c.1964+17G>T (Benign) | 0.200% | 0.810% | 0.610% | No | Multiple publications | |
| Ex61:c.10515C>A / p.S3505R (Benign) | 0.230% | 1.130% | 0.820% | No | Multiple publications | |||||||
| Ex66:c.11738G>A / p.R3913H (Benign) | 1.270% | 0.000% | 0.430% | No | AA MAF | |||||||
| Ex17:c.1587T>C / p.(=) (Benign) | 1.380% | 6.860% | 5.010% | Partial | EA MAF | |||||||
| Ex65:c.11525G>T / p.R3842L (Benign) | 0.360% | 2.430% | 1.730% | Partial | EA MAF | |||||||
| Ex61:c.10585G>C / p.E3529Q (Benign) | 3.950% | 0.010% | 1.350% | Partial | AA MAF | |||||||
| Rett syndrome | MECP2 | X Linked | Not specific | 0.012% | de novo | Ex4:c.1161C>T / p.(=) (Benign) | 0.030% | 0.000% | 0.010% | Partial | AA MAF | |
| Ex4:c.608C>T / p.T203M (Benign) | 0.000% | 0.060% | 0.040% | Partial | Multiple publications | |||||||
| Ex4:c.683C>G / p.T228S (Pathogenic) | 0.830% | 0.000% | 0.300% | Partial | RETT database | |||||||
| Kabuki syndrome | KMT2D (MLL2) | AD | Not specific | 0.003% | de novo | IVS31:c.8047-15C>T (Benign) | 0.000% | 0.020% | 0.020% | Partial | EA MAF | |
| Ex31:c.6836G>A / p.Gly2279E (Benign) | 0.000% | 0.120% | 0.080% | Partial | EA MAF | |||||||
| CHARGE syndrome | CHD7 | AD | Not specific | 0.010% | de novo | Ex2:c.309G>A / p.(=) (Benign) | 1.460% | 0.000% | 0.490% | Partial | AA MAF | |
| Ex31:c.6478G>A / p.A2160T (Benign) | 1.250% | 0.000% | 0.390% | Partial | AA MAF | |||||||
| Ex2:c.856A>G / p.R286Gly (Benign) | 0.780% | 0.000% | 0.250% | Partial | AA MAF | |||||||
| GJB2 associated hearing loss | GJB2 | AR | Not specific | 0.067% | 2.5% | c.35delG | Ex2:c.35delG (Pathogenic) | 0.090% | 1.080% | 0.740% | No | Multiple publications |
| Hemochromatosis | HFE | AR | All | 0.040% | 8.3% | p.C282Y | Ex4:c.845G>A / p.C282Y (Other Reportable) | 1.520% | 6.410% | 4.750% | No | Multiple publications |