Pathogenicity: Alzheimer's Disease : Benign
Clinical Phenotype:
Reference Assembly: GRCh37/hg19
Position: Chr1:227076671 T>C
dbSNP ID: rs61730652
Coding/Non-Coding: Coding
Mutation Type: Point, Silent
Codon Change: AGT to AGC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 8


This common, synonymous variant is found in the gnomAD variant database (frequency=0.01351; v2.1.1) and 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 (frequency=0.0073; Nov 2021). Although in the gnomAD database it is reported in many populations worldwide, it is particularly prevalent in individuals of African descent (allele count of 2,217, including 103 homozygotes), and absent from the East Asian population. 

The variant has been reported in two individuals with Alzheimer's disease (AD). It was first identified in an Italian with atypical early onset AD (Coppola et al., 2020). Fifty-one dementia-related genes, including APP, PSEN1, and PSEN2, were sequenced using next-generation sequencing. The patient, an APOE3 homozygote, developed apathy and language deficits at age 59. Over time, language impairment became worse and other symptoms arose, including psychomotor agitation, delusional ideation, and generalized motor slowness. At age 61, mixed pyramidal and extrapyramidal syndrome were diagnosed, mostly affecting the left side, and cortical sensory loss, as well as frontal release signs were observed. The patient had no family history of dementia.

The variant was subsequently identified in an individual of the Chinese Familial Alzheimer’s Disease Network (Jia et al., 2020). This carrier was homozygous for the APOE3 allele and had an age at onset of 57 years. The individual's family included two affected members, spanning two generations, with a mean age at onset of 68.5 years.

Neuropathological data are unavailable, but PET imaging of the Italian carrier showed diffuse uptake of an amyloid marker, and MRI revealed discrete, bilateral atrophy in temporo-insular cortices (Coppola et al., 2020). Moreover, FDG-PET showed severe and diffuse hypometabolism in the cortex, especially in the temporo-parietal cortices, precuneus, and posterior cingulate cortex, with the right side being particularly affected. Hypometabolism was also detected in the striatum, with the left side being more affected. CSF levels of progranulin were normal.

Biological Effect
The biological effects of this variant are unknown. Although its PHRED-scaled CADD score, which integrates diverse information in silico, was well below 20 (7.2; CADD v.1.6, Nov 2021) suggesting it is benign, Jia and colleageus noted it could potentially alter splicing (Jia et al., 2020).

Last Updated: 08 Nov 2021


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Paper Citations

  1. . Singular cases of Alzheimer's disease disclose new and old genetic "acquaintances". Neurol Sci. 2020 Oct 2; PubMed.
  2. . PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Singular cases of Alzheimer's disease disclose new and old genetic "acquaintances". Neurol Sci. 2020 Oct 2; PubMed.

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