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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:2

Conservation

PhyloP100: 9.05

Variant links:

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]

PSEN2 links:

ENSG00000288674 (HGNC:):

ENSG00000288674 links:

Genome browser will be placed here

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

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSEN2	NM_000447.3 link	c.422A>T	p.Asn141Ile	missense_variant	Exon 6 of 13	ENST00000366783.8	NP_000438.2	P49810-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSEN2	ENST00000366783.8 link	c.422A>T	p.Asn141Ile	missense_variant	Exon 6 of 13	5	NM_000447.3	ENSP00000355747.3		P49810-1
ENSG00000288674	ENST00000366779.6 link	n.422A>T		non_coding_transcript_exon_variant	Exon 6 of 32	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

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

Sep 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Feb 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 12, 2022

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3Other:1

Jan 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 21, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

VIB Department of Molecular Genetics, University of Antwerp

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 31, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

D;.;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;.;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.9

M;M;.;.

PrimateAI

Pathogenic

0.81

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over