ABCA1 p.Ser2046Asn
| Predicted by SNAP2: | A: D (85%), C: D (91%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (91%), N: D (91%), P: D (95%), Q: D (91%), R: D (95%), T: D (91%), V: D (95%), W: D (95%), Y: D (95%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, T: D, V: D, W: D, Y: D, |
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[hide] Whole exome sequencing combined with integrated va... Atherosclerosis. 2015 Jun;240(2):324-9. doi: 10.1016/j.atherosclerosis.2015.04.003. Epub 2015 Apr 7. Tada H, Kawashiri MA, Nohara A, Saito R, Tanaka Y, Nomura A, Konno T, Sakata K, Fujino N, Takamura T, Inazu A, Mabuchi H, Yamagishi M, Hayashi K
Whole exome sequencing combined with integrated variant annotation prediction identifies asymptomatic Tangier disease with compound heterozygous mutations in ABCA1 gene.
Atherosclerosis. 2015 Jun;240(2):324-9. doi: 10.1016/j.atherosclerosis.2015.04.003. Epub 2015 Apr 7., [PMID:25875382]
Abstract [show]
OBJECTIVE: Molecular diagnosis for subjects with extremely low HDL-C through candidate-gene approaches requires huge effort. Whole exome-sequencing (WES) has already shown approximately approximately 30% success in the diagnosis of Mendelian disorders. Moreover, novel in silico prediction software for the pathogenicity of novel missense variants named Combined Annotation Dependent Depletion (CADD) has recently been developed, enabling the objective integration of many diverse annotations into a single measure (C-score) for each variant. Here, we investigated whether WES combined with integrated variant annotation prediction could facilitate the molecular diagnosis of this rare condition. METHODS: WES was performed on 8 individuals including 2 individuals exhibiting extremely low HDL-C (2 mg/dl and 6 mg/dl), 2 unaffected family members, and 4 unrelated individuals as controls. We filtered out the following variants: 1) Benign variants predicted by SnpEff; 2) Minor allele frequency (MAF) > 1%; 3) Segregation unmatched for the recessive form of inheritance; 4) C-score < 10. RESULTS: Among 305,202 variants found in those individuals, we found 21,708 nonsense, missense, or splice site variants, of which 5192 were rare (MAF </= 1% or not reported). Filtering assuming a recessive pattern of inheritance, combined with the use of the C-score, successfully narrowed down the candidates to compound heterozygous mutations in the ABCA1 gene (c.6230C > A or p.P2077H/c.6137G > A or p.S2046N, and c.2842G > A or p.G948R/c.1130C > T or p.P377L). CONCLUSIONS: WES combined with integrated variant annotation prediction successfully identified asymptomatic Tangier disease with novel ABCA1 mutations. This comprehensive approach is useful to determine causative variants, especially in recessive inherited diseases.
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No. Sentence Comment
7 Filtering assuming a recessive pattern of inheritance, combined with the use of the C-score, successfully narrowed down the candidates to compound heterozygous mutations in the ABCA1 gene (c.6230C > A or p.P2077H/c.6137G > A or p.S2046N, and c.2842G > A or p.G948R/c.1130C > T or p.P377L).
X
ABCA1 p.Ser2046Asn 25875382:7:230
status: NEW94 Gray indicates the carrier of c.6137G > A or S2046N.
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ABCA1 p.Ser2046Asn 25875382:94:45
status: NEW104 Four out of seven variants (c.6230C > A or p.P2077H, c.6137G > A or p.S2046N, c.2842G > A or p.G948R, and c.1130C > T or p.P377L, all of those were variants in ABCA1 gene) were predicted to be damaging (scaled C-score > 10), which meant that those variants could be potentially causative mutations.
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ABCA1 p.Ser2046Asn 25875382:104:70
status: NEW139 Codon change Protein change Function CADD score Family (individual ID) chr5 140595355 PCDHB13 G T c.1660G > T A554S missense 3.305 Family 2 (LHDL4) chr6 1611407 FOXC1 G T c.728G > T A243S missense 4.256 Family 2 (LHDL4) chr9 107549232 ABCA1 C A c.6230C > A P2077H missense 18.61 Family 1 (LHDL1, LHDL3) chr9 107550268 ABCA1 G A c.6137G > A S2046N missense 36 Family 1 (LHDL2, LHDL3) chr9 107583774 ABCA1 G A c.2842G > A G948R missense 31 Family 2 (LHDL4) chr9 107599773 ABCA1 C T c.1130C > T P377L missense 25.9 Family 2 (LHDL4) chr22 38471068 PICK1 G A c.1177G > A G393R missense 2.236 Family 1 (LHDL1, LHDL2, LHDL3) Chr: chromosome, Pos: position, Ref: reference allele, Alt: alternate allele, CADD: combined annotation dependent depletion score, PCDHB13: Protocadherin beta-13, FOXC1: Forkhead box C1, ABCA1: ATP-binding cassette sub-family A member 1, PICK1: Protein interacting with C-kinase.
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ABCA1 p.Ser2046Asn 25875382:139:340
status: NEW