NM_000447.3:c.185G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R62C) has been classified as Uncertain significance.

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

Publications

57 publications found

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 Gene-Disease associations (from GenCC):

Alzheimer disease 4
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
early-onset autosomal dominant Alzheimer disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

PSEN2 links:

ENSG00000288674 (HGNC:):

ENSG00000288674 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 Benign/Likely_benign. ClinVar VariationId is 97995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2130 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSEN2	NM_000447.3 link	c.185G>A	p.Arg62His	missense_variant	Exon 5 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.185G>A	p.Arg62His	missense_variant	Exon 5 of 13	5	NM_000447.3	ENSP00000355747.3		P49810-1
ENSG00000288674	ENST00000366779.6 link	n.185G>A		non_coding_transcript_exon_variant	Exon 5 of 32	2		ENSP00000355741.2

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

GnomAD2 exomes

AF:

0.00861

AC:

2161

AN:

251116

AF XY:

0.00918

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 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

African (AFR)

AF:

0.0468

AC:

1568

AN:

33478

American (AMR)

AF:

0.00662

AC:

296

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0178

AC:

464

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0264

AC:

2278

AN:

86256

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.0250

AC:

144

AN:

5754

European-Non Finnish (NFE)

AF:

0.00116

AC:

1286

AN:

1112006

Other (OTH)

AF:

0.00906

AC:

547

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

397

793

1190

1586

1983

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

224

336

448

560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0140

AC:

2130

AN:

152284

Hom.:

Cov.:

AF XY:

0.0142

AC XY:

1054

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0398

AC:

1652

AN:

41538

American (AMR)

AF:

0.00843

AC:

129

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.0216

AC:

104

AN:

4820

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00194

AC:

132

AN:

68024

Other (OTH)

AF:

0.0166

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

102

203

305

406

508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00663

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

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

VIB Department of Molecular Genetics, University of Antwerp

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Sep 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PSEN2: BP4, BS1, BS2 -

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 24, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Alzheimer disease 4

Benign:3

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

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. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Dilated cardiomyopathy 1V

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely 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). 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

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

(source)

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;.;.

PhyloP100

-1.5

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over