Table 3.
List of novel CRB1 likeky pathogenic variants identified in the studied cohort
|
Nucleotide change |
AA change |
Protein |
Conservation |
SIFT score |
Polyphen score |
GD-GV score |
PROVEAN score |
Pathogenicity |
|---|---|---|---|---|---|---|---|---|
| Domain | ||||||||
|
Missense |
|
|
|
|
|
|
|
|
| c.1604 T > C |
p.Leu535Pro |
Lam AG1 |
HC |
0 |
1 |
Class C65 |
-6.5 |
Likely |
| c.1690G > T |
p.Asp564Tyr |
Lam AG1 |
HC |
0 |
1 |
Class C65 |
-8.2 |
Likely |
| c.1702C > T |
p.His568Tyr |
Lam AG1 |
HC |
0 |
0.999 |
Class C65 |
-5.0 |
Likely |
| c.2291G > A |
p.Arg764His |
Lam AG2 |
NC |
0.06 |
0.012 |
Class C0 |
-2.3 |
Uncertain a |
| c.2309 G > T |
p.Gly770Val |
Lam AG2 |
HC |
0 |
1 |
Class C65 |
-8.2 |
Likely |
| c.2696 G > C* |
p.Gly899Ala |
EGF13 |
HC |
0.1 |
0.996 |
Class C0 |
-4.5 |
Likely |
| c.3002A > T |
p.Ile1001Asn |
Lam AG3 |
MC |
0.0 |
0.850 |
Class C45 |
-5.5 |
Likely |
| c.3014 A > T |
p.Asp1005Val |
Lam AG3 |
WC |
0.02 |
0.996 |
Class C15 |
-5.0 |
Likely |
| c.3157 A > G |
p.Met1053Val |
Lam AG3 |
HC |
0 |
0.994 |
Class C15 |
-2.2 |
Likely |
| c.3299 T > C |
p.Ile1100Thr |
Lam AG3 |
C |
0 |
0.977 |
Class C25 |
-3.6 |
Likely |
| c.3482A > G |
p.Tyr1161Cys |
EGF15 |
MC |
0 |
0.999 |
Class C15 |
-6.1 |
Likely |
|
Nonsense |
|
|
|
|
|
|
|
|
| c.2416G > T |
p.Glu806* |
Lam AG2 |
Protein truncation, NMD |
|
|
|
|
|
| c.2465G > A |
p.Trp822* |
Lam AG2 |
Protein truncation, NMD |
|
|
|
|
|
| c.3152G > A |
p.Trp1051* |
Lam AG3 |
Protein truncation, NMD |
|
|
|
|
|
| c.3607 G > T |
p.Glu1203* |
EGF16 |
Protein truncation, NMD |
|
|
|
|
|
| c.3988G > T |
p.Glu1330* |
EGF19 |
Protein truncation, NMD |
|
|
|
|
|
| c.4168C > T |
p.Arg1390* |
C |
Protein truncation |
|
|
|
|
|
|
Frameshift indels |
|
|
|
|
|
|
|
|
| c.481dupG |
p.Ala161Glyfs*8 |
EGF4 |
Protein truncation, NMD |
|
|
|
|
|
| c.1147_1156del |
p.Cys383Serfs*66 |
EGF9 |
Protein truncation, NMD |
|
|
|
|
|
| c.2227delG |
p.Val743Serfs*11 |
Lam AG2 |
Protein truncation, NMD |
|
|
|
|
|
| c.2805dupA |
p.His935Glnfs*13 |
EGF14 |
Protein truncation, NMD |
|
|
|
|
|
| c.4000delG |
p.Val1334Trpfs*7 |
EGF19 |
Protein truncation, NMD |
|
|
|
|
|
|
Splicing |
|
|
|
|
|
|
|
|
| c.3749 + 1_3749 + 2del |
- |
EGF17 |
Splicing defect, NMD |
|
|
|
|
|
| c.3878 + 2insT |
Splicing |
EGF18 |
Splicing defect, NMD |
|
|
|
|
|
|
In-frame indel |
|
|
|
|
|
|
|
|
| c.2244_47delATC |
p.Ser749del |
Lam AG2 |
WC |
|
|
|
-11.453 |
Likely |
| c.498_506del | p.Ile167_Gly169del | EGF4 | Gly167: MC | -14.258 | Likely | |||
Nucleotide numbering is based on RefSeq DNA accession number NM_201253.1. Lam AG: Laminin AG-like domain, EGF: EGF-like domain, C: cytoplasmatic domain. Conservation of the amino acid substituted or deleted in 17 species was detailed. HC: Highly conserved, MC: Moderately conserved, WC: Weakly conserved, and NC: non-conserved residue. The amino acid substitution is predicted damaging by if the SIFT score is < = 0.05 and PROVEAN scores is < -2.5. Polyphen predict a non-synonymous variant as benign, possibly damaging, or probably damaging, if score is < 0.2, between 0.2 and 0.85 or > 0.85. GV: Grantham Variation; GD: Grantham distribution. Class C65: most likely pathogenic, Class C0: less likely pathogenic.
a This variant has been considered as likely pathogenic despite of poor conservation and less likely pathogenicity with four predictive tools. This variant was found associated with a second allele. It was absent in healthy control alleles but reported in ESP project (1/4405). Moreover, a known mutation Arg764Cys was reported in the same residue.