Mutations
PSEN2 A258T
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Overview
Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity
Criteria: PP3, BS1, BS2
Clinical
Phenotype: None
Position: (GRCh38/hg38):Chr1:226889034 G>A
Position: (GRCh37/hg19):Chr1:227076735 G>A
dbSNP ID: rs148238688
Coding/Non-Coding: Coding
DNA
Change: Substitution
Expected RNA
Consequence: Substitution
Expected Protein
Consequence: Missense
Codon
Change: GCC to ACC
Reference
Isoform: PSEN2 Isoform 1 (448 aa)
Genomic
Region: Exon 8
Findings
This variant was detected in a control individual in a study assessing 72 AD cases and 58 controls (Frigerio et al., 2015). There was no family history of dementia. The age of the mutation carrier was not reported, nor were details regarding his or her cognitive health. Classification as a control was based on a lack of significant AD pathology in the brain. Moreover, in HEX, a database of variants from people age 60 or older who did not have a neurodegenerative disease diagnosis or disease-associated neuropathology at the time of death, it was present with an allele count of one in a total of 954 alleles (Nov 2021).
This variant was also found in the gnomAD database with an allele count of 34 and a global frequency of 0.0001 (v2.1.1, Nov 2021). Most carriers were non-Finnish Europeans.
Neuropathology
Not applicable.
Biological Effect
Unknown. In silico, the A258T variant was predicted to be probably damaging by PolyPhen2 (Frigerio et al., 2015) and its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021).
Pathogenicity
Alzheimer's Disease : Benign
This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.
PP3-P
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.
BS1-S
Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database. A258T: Most carriers are of European ancestry.
BS2-S
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.
| Pathogenic (PS, PM, PP) | Benign (BA, BS, BP) | |||||
|---|---|---|---|---|---|---|
| Criteria Weighting | Strong (-S) | Moderate (-M) | Supporting (-P) | Supporting (-P) | Strong (-S) | Strongest (BA) |
Last Updated: 22 Feb 2022
References
Other Citations
Further Reading
No Available Further Reading
Protein Diagram
Primary Papers
- Sala Frigerio C, Lau P, Troakes C, Deramecourt V, Gele P, Van Loo P, Voet T, De Strooper B. On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients. Alzheimers Dement. 2015 Apr 29; PubMed.
Other mutations at this position
Alzpedia
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