rs63750215

chr1-226885603-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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. N141Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PSEN2 NM_000447.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:2
• 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]

ACMG classification

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

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN2	NM_000447.3	c.422A>T	p.Asn141Ile	missense_variant	6/13	ENST00000366783.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN2	ENST00000366783.8	c.422A>T	p.Asn141Ile	missense_variant	6/13	5	NM_000447.3	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alzheimer disease 4 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Aug 12, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2011	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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). ClinVar contains an entry for this variant (Variation ID: 8845). 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. Experimental studies have shown that this missense change affects PSEN2 function (PMID: 8986743, 9050898, 15663477, 16959576, 20634584, 21234330, 22115042, 22249458). For these reasons, this variant has been classified as Pathogenic. -
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 Pathogenic:3 Other:1

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	May 01, 2019	Not found in the total gnomAD dataset, and the data is high quality (0/282490 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Statistically associated with disease in multiple families (p<0.0001). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;.;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M;M;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.3	D;D;D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Uncertain	0.052	T;T;D;D
Polyphen		0.93	P;.;.;.
Vest4		0.96
MutPred		0.83		Loss of catalytic residue at S138 (P = 0.3572);Loss of catalytic residue at S138 (P = 0.3572);.;.;
MVP		0.99
MPC		0.90
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.89
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63750215; hg19: chr1-227073304;