Gene Validity Curation

CABP2 - nonsyndromic genetic deafness

Gene: CABP2 (HGNC:1385)
Classification - 02/06/2020
Disease: nonsyndromic genetic deafness (MONDO_0019497)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hearing Loss EP
Evidence Summary: CABP2 was first reported in relation to autosomal recessive nonsyndromic hearing loss in humans as early as 2012 (Schrauwen et al., PMID: 22981119). At least 4 unique variants (splice-site, nonsense, and missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 4 probands in 4 publications (PMID: 22981119, 26226137, 28183797, 31661684). Variants in this gene segregated with disease in at least 12 additional family members. This gene-disease association is supported by animal models, expression studies, and in vitro function studies. In summary, CABP2 is definitively associated with autosomal recessive nonsyndromic hearing loss.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 3
5
5.5
Schrauwen I et al. 2012 Oct 5 (PMID:22981119); Bademci G et al. 2016 Apr (PMID:26226137); Picher MM et al. 2017 Feb 28 (PMID:28183797);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
0.5
Koohiyan M et al. 2019 Oct 29 (PMID:31661684);
Segregation Evidence   Summed LOD Family Count 3 3  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 8.77 1
Schrauwen I et al. 2012 Oct 5 (PMID:22981119);
Total Summed LOD Score 8.77    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 8.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
2
Picher MM et al. 2017 Feb 28 (PMID:28183797);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 3 1.5
Picher MM et al. 2017 Feb 28 (PMID:28183797); Cui G et al. 2007 Dec 15 (PMID:17947313); Yang T et al. 2016 Jan 25 (PMID:26809054);
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 2 1
Schrauwen I et al. 2012 Oct 5 (PMID:22981119);
Models Non-human model organism 2 0 - 4 4 2 3 3
Picher MM et al. 2017 Feb 28 (PMID:28183797); Yang T et al. 2018 July (PMID:29661613);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 8.5 6 14.5 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
02/06/2020
EXPERT CURATION (DATE)
Definitive
02/06/2020
EVIDENCE SUMMARY
CABP2 was first reported in relation to autosomal recessive nonsyndromic hearing loss in humans as early as 2012 (Schrauwen et al., PMID: 22981119). At least 4 unique variants (splice-site, nonsense, and missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 4 probands in 4 publications (PMID: 22981119, 26226137, 28183797, 31661684). Variants in this gene segregated with disease in at least 12 additional family members. This gene-disease association is supported by animal models, expression studies, and in vitro function studies. In summary, CABP2 is definitively associated with autosomal recessive nonsyndromic hearing loss.