rs139972151

Positions:

chr1-226883771-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1BP4BP6BS1BS2

The NM_000447.3(PSEN2):c.208G>A(p.Gly70Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

PSEN2
NM_000447.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 3.07

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 -8 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=0.40273646).

BP6

Variant 1-226883771-G-A is Benign according to our data. Variant chr1-226883771-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 192129.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000458 (67/1461866) while in subpopulation NFE AF= 0.0000567 (63/1112008). AF 95% confidence interval is 0.0000452. There are 0 homozygotes in gnomad4_exome. There are 32 alleles in male gnomad4_exome subpopulation. Median coverage is 43. This position pass quality control queck.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSEN2	NM_000447.3 linkuse as main transcript	c.208G>A	p.Gly70Arg	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.208G>A	p.Gly70Arg	missense_variant	5/13	5	NM_000447.3	ENSP00000355747	P4	P49810-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251294

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000458

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000567

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 29, 2021	The PSEN2 c.208G>A; p.Gly70Arg variant (rs139972151) has been described in at least two individuals who had a clinical diagnosis of Alzheimer’s disease, but no additional clinical information was available (Wojtas 2012, see link to Alzheimer’s Association International Conference (AAIC) 2019 abstract). This variant contains an entry in ClinVar (Variation ID: 192129), and is found in the non-Finnish European population with an allele frequency of 0.011% (14/129028 alleles) in the Genome Aggregation Database. The glycine at codon 70 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.456). However, given the lack of clinical and functional data, the significance of the p.Gly70Arg variant is uncertain at this time. REFERENCES Wojtas A et al. C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic. Am J Neurodegener Dis. 2012;1(1):107-18. PMID: 23383383. Link to AAIC 2019 P3-120 abstract: https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1016/j.jalz.2019.06.3148 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PSEN2 p.Gly70Arg variant was identified in 1 of 454 proband chromosomes (frequency: 0.0022) from a cohort of 227 unrelated probands clinically diagnosed for Alzheimer disease with symptoms occuring before 70 years old (Wojtas_2012_PMID:23383383). The variant was identified in dbSNP (ID: rs139972151) and ClinVar (classified as likely benign by Biesecker Lab). The variant was identified in control databases in 17 of 282688 chromosomes at a frequency of 0.00006014 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 14 of 129028 chromosomes (freq: 0.000109), Latino in 2 of 35436 chromosomes (freq: 0.000056) and South Asian in 1 of 30616 chromosomes (freq: 0.000033), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. The p.Gly70 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

PSEN2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 26, 2023

The PSEN2 c.208G>A variant is predicted to result in the amino acid substitution p.Gly70Arg. This variant was reported in a patient with early-onset Alzheimer's disease (Wojtas et al. 2012. PubMed ID: 23383383) and as a likely benign variant in a study of patients with coronary artery disease risk (Ng et al. 2013. PubMed ID: 23861362). It is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Alzheimer disease 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 26, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with Alzheimer disease (PMID: 23383383). ClinVar contains an entry for this variant (Variation ID: 192129). This variant is present in population databases (rs139972151, ExAC 0.009%). This sequence change replaces glycine with arginine at codon 70 of the PSEN2 protein (p.Gly70Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.046

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.;.;.;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.078

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.89

D;D;D;.;D

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.40

T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.90

L;.;L;.;.

MutationTaster

Benign

0.99

D;D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.33

N;N;N;N;.

REVEL

Uncertain

0.46

Sift

Benign

0.12

T;T;T;T;.

Sift4G

Benign

0.28

T;T;T;T;T

Polyphen

0.010

B;.;.;.;.

Vest4

0.43

MutPred

0.26

Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);.;.;

MVP

0.97

MPC

0.31

ClinPred

0.080

GERP RS

4.4

Varity_R

0.061

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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