Mutations

PSEN2 I100I

Overview

Pathogenicity: Alzheimer's Disease : Likely Benign
ACMG/AMP Pathogenicity Criteria: BS1
Clinical Phenotype: Late-onset
Position: (GRCh38/hg38):Chr1:226883863 C>T
Position: (GRCh37/hg19):Chr1:227071564 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Silent
Codon Change: ATC to ATT
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 5

Findings

This variant was reported in a preprint that analyzed data from the Alzheimer’s Disease Sequencing Project (ADSP), including whole-exome and whole-genome sequences from 13,825 late-onset AD cases and 14,715 controls. The variant was identified in two AD cases and was absent from controls (Wang et al., 2023, suppl table e-3).

As reported in the gnomAD variant database, the global frequency of this variant is 0.000064 including 99 heterozygotes (gnomAD v4.0.0, Feb 2024). Although most heterozygotes are of European ancestry (54 individuals; frequency: 0.000048), frequencies are substantially higher in individuals of Middle Eastern (0.0016), Admixed American (0.00038), and South Asian (0.00011) ancestries.

Neuropathology
Neuropathological data are unavailable.

Biological Effect
The biological effect of this variant is unknown, but it is a silent mutation and in silico it was predicted to be benign. Its PHRED-scaled CADD score was 6.52 (CADD v1.7, Feb 2024).

Pathogenicity

Alzheimer's Disease : Likely Benign

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  I100I: Frequency is particularly high in individuals of Middle Eastern ancestry.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 13 Feb 2024

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References

Paper Citations

  1. Wang D, Scalici A, Wang Y, Lin H, Pitsillides A, Heard-Costa N, Cruchaga C, Ziegemeier E, Bis JC, Fornage M, Boerwinkle E, DeJager PL, Wijsman E, Dupuis J, Renton AE, Seshadri S, Goate AM, The Alzheimer's Disease Sequencing Project, DeStefano AL, Peloso GM. Frequency of Variants in Mendelian Alzheimer's Disease Genes within the Alzheimer's Disease Sequencing Project (ADSP). 2023 Oct 25 10.1101/2023.10.24.23297227 (version 1) medRxiv.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Wang D, Scalici A, Wang Y, Lin H, Pitsillides A, Heard-Costa N, Cruchaga C, Ziegemeier E, Bis JC, Fornage M, Boerwinkle E, DeJager PL, Wijsman E, Dupuis J, Renton AE, Seshadri S, Goate AM, The Alzheimer's Disease Sequencing Project, DeStefano AL, Peloso GM. Frequency of Variants in Mendelian Alzheimer's Disease Genes within the Alzheimer's Disease Sequencing Project (ADSP). 2023 Oct 25 10.1101/2023.10.24.23297227 (version 1) medRxiv.

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