Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP3, BS1, BS3
Clinical Phenotype: None
Position: (GRCh38/hg38):Chr1:226889016 G>A
Position: (GRCh37/hg19):Chr1:227076717 G>A
dbSNP ID: rs138836272
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCG to ACG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 8

Findings

This variant was found in two African individuals from the Mandenka and Yoruba populations (Guerreiro et al., 2010). It has also been reported in the gnomAD variant database with an allele count of 64 and a global frequency of 0.0002 (v2.1.1, Nov 2021). More than half of the 64 heterozygotes in this database are of African ancestry (36), and the frequency in this population is 0.0014.

Neuropathology

Not applicable.

Biological Effect

Mouse neuroblastoma cells expressing this variant secreted moderately reduced levels of both Aβ42 and Aβ40 compared with cells expressing wild-type PSEN2. The Aβ42/Aβ40 ratio was similar to controls (Hsu et al., 2020). This variant is predicted to alter a residue in the sixth transmembrane region of PSEN2. The residue is conserved in PSEN1 (A246) and two pathogenic mutations have been reported at the corresponding residue (PSEN1 A246E and A246P). In silico analyses predicted the PSEN2 A252T substitution to be possibly damaging (Polyphen) and tolerated (SIFT), with a PHRED-scaled CADD score, which integrates diverse information in silico, above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021). Hsu et al. classified the mutation as not pathogenic and possibly protective.

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.

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References

Mutations Citations

1. PSEN1 A246P

Paper Citations

1. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
2. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

Other Citations

1. A246E

Further Reading

No Available Further Reading