CASP8 M1T - GET-Evidence



(CASP8 Met1Thr)

Short summary

Probably benign. Although start codons can be extremely disruptive and this gene is implicated in a rare disease (autoimmune lymphoproliferative syndrome), the allele frequency for this variant (2-3%) is high enough to contradict such a strong pathogenic effect. This may be because the gene has many other transcripts that do not include this position as exonic.

Variant evidence
Computational -1

Start codon mutation is usually very disruptive

Functional -
Case/Control 2

Allele frequency contradicts a high penetrance pathogenic effect

Familial -
Clinical importance
Severity -
Treatability -
Penetrance -


Low clinical importance, Uncertain benign

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

Inheritance pattern


Summary of published research, and additional commentary

No known publications, found heterozygously in 4 out of 64 PGP + public genomes (allele frequency of 3.1%). Because we are evaluating variants as they are seen in genomes, this is a biased estimate of frequency — a less biased estimate might be 3 out of 63 (allele frequency 2.4%). This is a start codon mutation and therefore predicted to be extremely disruptive through disrupting proper initiation of translation within the ribosome. A different mutation in this gene (Arg248Try) has been reported to cause autoimmune lymphoproliferative syndrome by one group (Chun et al.) but, as far as we know, there are no other publications linking the gene to inherited disease. The same group provided a large amount of functional characterization of the variant supporting the Arg248Try as having a damaging effect.

With an allele frequency of 2.4%, 1 in 1500 to 2000 individuals are predicted to be homozygous. The disease, on the other hand, is expected to be quite rare — this implies that either this variant does not have a significant disruptive effect (possibly due to alternative splicing or an alternative start codon), the disease is severely underdiagnosed (possibly less extreme), or that the hypothesis of Chun et al for this gene as being causal was mistaken. We suspect the first possibility is the case, as there are several other transcripts recorded for this gene, many of which do not include this position as an exon.

Allele frequency

  • C @ chr2:202122956: 3.1% (303/9760) in EVS
  • C @ chr2:201831200: 3.1% (4/128) in GET-Evidence
  • Frequency shown in summary reports: 3.1% (303/9760)


Chun HJ, Zheng L, Ahmad M, Wang J, Speirs CK, Siegel RM, Dale JK, Puck J, Davis J, Hall CG, Skoda-Smith S, Atkinson TP, Straus SE, Lenardo MJ. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature. 2002 Sep 26;419(6905):395-9. PubMed PMID: 12353035.



hu43860C - CGI sample GS00253-DNA_A01_200_37
het C @ chr2:202122956


hu44DCFF - CGI sample GS01669-DNA_C07 from PGP sample 74521372
het C @ chr2:202122956


huFFAD87 - CGI sample GS01669-DNA_H05 from PGP sample 10971581
het C @ chr2:202122956


GS06994 - var-GS06994-1100-36-ASM
het C @ chr2:201831201


GS12004 - var-GS12004-1100-36-ASM
het C @ chr2:201831201


GS19834 - var-GS19834-1100-36-ASM
het C @ chr2:201831201


Other external references

  • rs3769824
  • Score: 0.999 (probably damaging)

Other in silico analyses

  • NBLOSUM100 score = 2
  • GET-Evidence autoscore = 3

Edit history

Gene search

"GENE" or "GENE A123C":

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