Dear gnomAD Team,
I hope this message finds you well. I am writing to request clarification regarding a variant in PRKAG2 observed in gnomAD v4.1.0. Specifically, the variant:
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Variant ID: 7-151595309-A-AT
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HGVS: p.Trp258LeufsTer9
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Annotation: frameshift, predicted LoF (LC pLoF)
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Allele Count: ~1.15M
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Allele Frequency: ~0.75
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Homozygotes: >430,000
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LoF Curation: “Benign/Likely benign”
Given that PRKAG2 is a well-established disease gene associated with cardiac syndrome, the extremely high allele frequency and the very large number of homozygous carriers raise questions about the biological relevance of this predicted LoF call. I am hoping to better understand:
Whether this region is subject to alignment or annotation artifacts in gnomAD.
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Whether gnomAD recommends excluding this variant when assessing PRKAG
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LoF constraint or interpreting LoF burden.
Or do you have any comments on such abnormal high frequency homozygous for pLoF carriers in the biobank.
Any insights or documentation you can share would be greatly appreciated. We are conducting gene-level evaluations and want to ensure our interpretation aligns with gnomAD’s curation framework.
Thank you very much for your time and for maintaining such an invaluable community resource.
Best,
Shicheng
