chr1-226885603-A-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000447.3(PSEN2):c.422A>T(p.Asn141Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N141D) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 31)
Consequence
PSEN2
NM_000447.3 missense
NM_000447.3 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 9.05
Genes affected
PSEN2 (HGNC:9509): (presenilin 2) Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1 or PSEN2) or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor such that, they either directly regulate gamma-secretase activity, or themselves act are protease enzymes. Two alternatively spliced transcript variants encoding different isoforms of PSEN2 have been identified. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PM1
In a transmembrane_region Helical (size 20) in uniprot entity PSN2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000447.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
Variant 1-226885603-A-T is Pathogenic according to our data. Variant chr1-226885603-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 8845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-226885603-A-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PSEN2 | ENST00000366783.8 | c.422A>T | p.Asn141Ile | missense_variant | Exon 6 of 13 | 5 | NM_000447.3 | ENSP00000355747.3 | ||
| ENSG00000288674 | ENST00000366779.6 | n.422A>T | non_coding_transcript_exon_variant | Exon 6 of 32 | 2 | ENSP00000355741.2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Alzheimer disease 4 Pathogenic:4Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 16, 2023 | This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 141 of the PSEN2 protein (p.Asn141Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early onset Alzheimer's disease (PMID: 7638622, 7651536, 16533963, 18833506, 19073399, 20457965, 24928124, 26166204). It is commonly reported in individuals of German ancestry (PMID: 7651536, 16533963, 18833506, 19073399, 20457965, 24928124). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PSEN2 function (PMID: 8986743, 9050898, 15663477, 16959576, 20634584, 21234330, 22115042, 22249458). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PSEN2 protein function. ClinVar contains an entry for this variant (Variation ID: 8845). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 29, 2024 | Variant summary: PSEN2 c.422A>T (p.Asn141Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251120 control chromosomes (gnomAD). c.422A>T has been reported in the literature in multiple individuals affected with Alzheimer Disease (e.g. Leverenz_2006, Muchnik_2015). These data indicate that the variant is very likely to be associated with disease. Publications report experimental evidence evaluating an impact on protein function, finding that the variant alters PSEN2 function (e.g. Tu_2006, Nam_2022). The following publications have been ascertained in the context of this evaluation (PMID: 26166204, 16533963, 35418126, 16959576). ClinVar contains an entry for this variant (Variation ID: 8845). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2011 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Aug 12, 2022 | - - |
not provided Pathogenic:3Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 31, 2022 | Published functional studies demonstrate N141I resulted in impaired secretase activity as well as exaggerated inflammatory cytokine release, NFKB activity, and A-beta internalization (Fung et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20457965, 7651536, 33084218, 30412492, 31020001, 25323700, 24594196, 24093083, 20301414, 22805202, 21911706, 22505025, 21559247, 20333730, 7638622, 16533963, 15776278, 16155344, 15663477, 15389756, 9813158, 10846187, 8939861, 7550356, 9050898, 8986743, 22115042, 23365231, 16959576, 20634584, 21234330, 22249458, 30954774, 26166204, 9450781, 24928124, 8661049, 19073399, 18833506, 20375137, 30822648, 32087291, 32032730, 32741831) - |
| not provided, no classification provided | literature only | VIB Department of Molecular Genetics, University of Antwerp | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 21, 2023 | This variant associates with Alzheimer disease in multiple families. This variant has not been reported in large, multi-ethnic general populations. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 9050898, 10846187, 15663477, 22249458, 31020001, 35992913) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;D;.
Sift4G
Uncertain
T;T;D;D
Polyphen
P;.;.;.
Vest4
MutPred
Loss of catalytic residue at S138 (P = 0.3572);Loss of catalytic residue at S138 (P = 0.3572);.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at