1-226885570-C-T

Position:

chr1-226885570-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM1BP4BP6_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 (★★).

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:6O: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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PM1

In a chain Presenilin-2 NTF subunit (size 296) in uniprot entity PSN2_HUMAN there are 12 pathogenic changes around while only 5 benign (71%) in NM_000447.3

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/exons	MANE	Protein	UniProt
PSEN2	NM_000447.3 linkuse as main transcript	c.389C>T	p.Ser130Leu	missense_variant	6/13	ENST00000366783.8	NP_000438.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSEN2	ENST00000366783.8 linkuse as main transcript	c.389C>T	p.Ser130Leu	missense_variant	6/13	5	NM_000447.3	ENSP00000355747	P4	P49810-1

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:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alzheimer disease 4

Pathogenic:1Benign:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2006	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -

Dilated cardiomyopathy 1V

Pathogenic:1Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2006	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 30, 2020

- -

PSEN2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2020

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

Likely benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

not provided

Other:1

not provided, no classification provided

literature only

VIB Department of Molecular Genetics, University of Antwerp

- -

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;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A

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