COL5A2 P460S - GET-Evidence

Curation:
Currentness:

COL5A2 P460S

(COL5A2 Pro460Ser)


Short summary

Tentatively benign. Although predicted to be damaging by Polyphen 2, this variant is seen in 2 out of 62 PGP & public genomes. OMIM lists other more disruptive variants (frameshift & nonsense) as reported to cause Ehlers-Danlos syndrome when homozygous.

Variant evidence
Computational

Polyphen 2 predicts damaging effect, but variants listed by OMIM for Ehlers-Danlos are more severe (frameshift/nonsense)

Functional -
Case/Control 1

Estimated homozygous rate of 1 in 4,000 is inconsistent with reported incidence of Ehlers-Danlos (1 in 20,000 to 50,000), although more observations are needed to establish a stastically significant difference.

See unpublished research (below).

Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Low clinical importance, Uncertain benign

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

Inheritance pattern

unknown

Summary of published research, and additional commentary

Ehlers-Danlos syndrome has a prevalence of 1 in 20,000 to 1 in 50,000. Using this, we can estimate the maximum allele frequency of some unknown pathogenic variant causing this disease to be around (1/50,000)^0.5 = 0.0045. The chances of seeing a variant with 0.45% allele frequency twice in 128 randomly chosen variants is p = 0.0205.

Note, however, that we are evaluating this variant because it is present in one of the genomes — a less biased estimator would exclude that genome, leaving us with 1 in 127 random observations, this has much lower statistical significance for differing from the frequency=0.45% hypothesis (p = 0.112).

Allele frequency

  • A @ chr2:189932764: 4.0% (431/10758) in EVS
  • A @ chr2:189641008: 1.6% (2/124) in GET-Evidence
  • Frequency shown in summary reports: 4.0% (431/10758)

Publications
 

Genomes
 

 

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het A @ chr2:189932764

 

hu92C40A - CGI sample GS01175-DNA_G03 from PGP sample 92527586
het A @ chr2:189932764

 

huD37D14 - CGI sample GS01175-DNA_A04 from PGP sample 13272228
het A @ chr2:189932764

 

GS06994 - var-GS06994-1100-36-ASM
het A @ chr2:189641009

 

Other external references
 

    dbSNP
  • rs35830636
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.966 (probably damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 3
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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