rs58973334

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000447.3(PSEN2):c.185G>A(p.Arg62His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 1,614,112 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 35 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 121 hom. )

Consequence

PSEN2
NM_000447.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: -1.50

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 -18 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=0.0026604533).

BP6

Variant 1-226883748-G-A is Benign according to our data. Variant chr1-226883748-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 97995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-226883748-G-A is described in Lovd as [Benign]. Variant chr1-226883748-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.014 (2130/152284) while in subpopulation AFR AF= 0.0398 (1652/41538). AF 95% confidence interval is 0.0382. There are 35 homozygotes in gnomad4. There are 1054 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2130 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSEN2	NM_000447.3 linkuse as main transcript	c.185G>A	p.Arg62His	missense_variant	5/13	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.185G>A	p.Arg62His	missense_variant	5/13	5	NM_000447.3	ENSP00000355747	P4	P49810-1

Frequencies

GnomAD3 genomes

AF:

0.0139

AC:

2120

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0396

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00844

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0214

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00194

Gnomad OTH

AF:

0.0167

GnomAD3 exomes

AF:

0.00861

AC:

2161

AN:

251116

Hom.:

AF XY:

0.00918

AC XY:

1247

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.0402

Gnomad AMR exome

AF:

0.00645

Gnomad ASJ exome

AF:

0.0179

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0247

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00244

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.00451

AC:

6595

AN:

1461828

Hom.:

121

Cov.:

AF XY:

0.00525

AC XY:

3818

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0468

Gnomad4 AMR exome

AF:

0.00662

Gnomad4 ASJ exome

AF:

0.0178

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0264

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00116

Gnomad4 OTH exome

AF:

0.00906

GnomAD4 genome

AF:

0.0140

AC:

2130

AN:

152284

Hom.:

Cov.:

AF XY:

0.0142

AC XY:

1054

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0398

Gnomad4 AMR

AF:

0.00843

Gnomad4 ASJ

AF:

0.0199

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0216

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00194

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.00440

Hom.:

Bravo

AF:

0.0147

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0374

AC:

165

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00988

AC:

1200

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.00305

EpiControl

AF:

0.00451

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	PSEN2: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 24, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Alzheimer disease 4

Benign:3

Likely benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Benign, for Alzheimer disease 4, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:15663477). BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS1-Supporting => BS1 downgraded in strength to supporting. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	- -

Dilated cardiomyopathy 1V

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Alzheimer disease

Benign:1

Benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Benign

8.0

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.72

T;T;T;.;T

MetaRNN

Benign

0.0027

T;T;T;T;T

MetaSVM

Uncertain

0.77

MutationAssessor

Benign

0.20

N;.;N;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.4

N;N;N;N;.

REVEL

Uncertain

0.29

Sift

Benign

0.21

T;T;T;T;.

Sift4G

Benign

0.23

T;T;T;T;T

Polyphen

0.0010

B;.;.;.;.

Vest4

0.083

MVP

0.82

MPC

0.30

ClinPred

0.0090

GERP RS

-4.6

Varity_R

0.021

gMVP

0.22

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