COL9A2 T246M - GET-Evidence

Curation:
Currentness:

COL9A2 T246M

(COL9A2 Thr246Met)


Short summary

Probably benign.

Variant evidence
Computational -
Functional -
Case/Control 5

Seen in controls as well as cases. Strong statistical difference from a hypothetical dominant disease-causing variant with moderate penetrance (p=1.34*10^-7)

See Czarny-Ratajczak M et al. 2001 (11565064), unpublished research (below).

Familial

No familial data.

 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Low clinical importance, Likely benign

(The "low clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

Other variants in this gene are implicated in causing multiple epiphyseal dysplasia in a dominant manner, but this variant has been seen in several random controls — 2 out of 98 control alleles reported by Czarny-Ratajczak et al. and 3 out of 128 PGP + public genome alleles. Genetests gives the prevalence of this disease as 1 in 10,000, but notes that this is likely an underestimate due to underdiagnosis: http://www.ncbi.nlm.nih.gov/books/NBK1123/ Variants implicated to date have been fully or highly penetrance.

To test the significance of findings in controls, we compare our observations against the predicted allele frequency for a hypothetical variant with moderate (5%) penetrance responsible for half of all cases (1 in 1,000 carriers, 1 in 20,000 affected) — such a variant would have an allele frequency in the general population of .05%. Combining Czarny-Ratajczak et al and PGP + public data, the chances of seeing such a rare variant (with .05% frequency) 5 or more times in 226 alleles is p=1.34*10^-7.

Allele frequency

  • A @ chr1:40775937: 2.5% (272/10758) in EVS
  • A @ chr1:40548523: 2.3% (3/128) in GET-Evidence
  • Frequency shown in summary reports: 2.5% (272/10758)

Publications
 

Czarny-Ratajczak M, Lohiniva J, Rogala P, Kozlowski K, Perälä M, Carter L, Spector TD, Kolodziej L, Seppänen U, Glazar R, Królewski J, Latos-Bielenska A, Ala-Kokko L. A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity. Am J Hum Genet. 2001 Nov;69(5):969-80. Epub 2001 Sep 14. PubMed PMID: 11565064; PubMed Central PMCID: PMC1274373.

Listed in a table of variants found in both cases and controls and, because of this, judged “likely to be neural” by the authors. This variant was seen in 4 out of 66 case alleles and 2 out of 98 control alleles.

Genomes
 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het A @ chr1:40775937

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
het A @ chr1:40775937

 

 

GS19649 - var-GS19649-1100-36-ASM
het A @ chr1:40548524

 

Other external references
 

    dbSNP
  • rs2228565
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi

Other in silico analyses
 

  • NBLOSUM100 score = 2
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

Log in