rs63750197

Variant names:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4BP6_Very_StrongBS1BS2

The NM_000447.3(PSEN2):c.389C>T(p.Ser130Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0012 in 1,614,032 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S130S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00071 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0013 ( 3 hom. )

Consequence

PSEN2
NM_000447.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2B:7O:1

Conservation

PhyloP100: 4.68

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 Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3652564).

BP6

Variant 1-226885570-C-T is Benign according to our data. Variant chr1-226885570-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 8852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-226885570-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000709 (108/152252) while in subpopulation NFE AF= 0.00122 (83/68012). AF 95% confidence interval is 0.00101. There are 0 homozygotes in gnomad4. There are 55 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 108 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSEN2	NM_000447.3 link	c.389C>T	p.Ser130Leu	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.389C>T	p.Ser130Leu	missense_variant	Exon 6 of 13	5	NM_000447.3	ENSP00000355747.3		P49810-1
ENSG00000288674	ENST00000366779.6 link	n.389C>T		non_coding_transcript_exon_variant	Exon 6 of 32	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes

AF:

0.000710

AC:

108

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000677

AC:

170

AN:

251112

Hom.:

AF XY:

0.000722

AC XY:

AN XY:

135740

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00121

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.00125

AC:

1830

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

915

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000783

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00155

Gnomad4 OTH exome

AF:

0.000994

GnomAD4 genome

AF:

0.000709

AC:

108

AN:

152252

Hom.:

Cov.:

AF XY:

0.000739

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00122

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00123

Hom.:

Bravo

AF:

0.000627

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000634

AC:

EpiCase

AF:

0.00131

EpiControl

AF:

0.00166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:2Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alzheimer disease 4

Pathogenic:1Benign:2

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dilated cardiomyopathy 1V

Pathogenic:1Benign:1

Dec 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified

Benign:2

Oct 25, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PSEN2 c.389C>T (p.Ser130Leu) 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 allele was found at a frequency of 0.0012 in 1607058 control chromosomes, predominantly at a frequency of 0.0015 within the Non-Finnish European subpopulation in the gnomAD database (v4.1 dataset), including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in PSEN2 causing Alzheimer Disease 4 phenotype. c.389C>T has been reported in the literature in individuals affected with Alzheimer Disease (e.g. Tedde_2003). However, at least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated that the variant didn't alter amyloid beta (Abeta) peptide generation from beta-amyloid precursor protein (APP), suggesting that the variant represent a polymorphisms rather than disease-causing mutation (Walker_2005). In addition, the variant was also reported in individuals affected with idiopathic dilated cardiomyopathy (Li_2006), however current evidence is not sufficient to support the association of PSEN2 with this phenotype. The following publications have been ascertained in the context of this evaluation (PMID: 14623725, 15663477, 7186461, 20375137). ClinVar contains an entry for this variant (Variation ID: 8852). Based on the evidence outlined above, the variant was classified as likely benign. -

Dec 30, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PSEN2-related disorder

Benign:1

May 15, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Alzheimer disease

Benign:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Other:1

VIB Department of Molecular Genetics, University of Antwerp

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;.;.;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;.;D

M_CAP

Pathogenic

0.77

MetaRNN

Benign

0.37

T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;M;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.5

D;D;D;.

REVEL

Pathogenic

0.76

Sift

Uncertain

0.012

D;D;D;.

Sift4G

Uncertain

0.020

D;D;D;D

Polyphen

0.95

P;.;.;.

Vest4

0.74

MVP

0.98

MPC

0.60

ClinPred

0.18

GERP RS

5.1

Varity_R

0.56

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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