1-226882036-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000447.3(PSEN2):c.129C>T(p.Asn43Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 1,613,682 control chromosomes in the GnomAD database, including 213,053 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 18350 hom., cov: 33)

Exomes 𝑓: 0.51 ( 194703 hom. )

Consequence

PSEN2
NM_000447.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.345

Publications

26 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 1-226882036-C-T is Benign according to our data. Variant chr1-226882036-C-T is described in ClinVar as Benign. ClinVar VariationId is 256180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.345 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSEN2	NM_000447.3 link	c.129C>T	p.Asn43Asn	synonymous_variant	Exon 4 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.129C>T	p.Asn43Asn	synonymous_variant	Exon 4 of 13	5	NM_000447.3	ENSP00000355747.3		P49810-1
ENSG00000288674	ENST00000366779.6 link	n.129C>T		non_coding_transcript_exon_variant	Exon 4 of 32	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes

AF:

0.486

AC:

73822

AN:

152032

Hom.:

18340

Cov.:

show subpopulations

Gnomad AFR

AF:

0.389

Gnomad AMI

AF:

0.573

Gnomad AMR

AF:

0.525

Gnomad ASJ

AF:

0.612

Gnomad EAS

AF:

0.412

Gnomad SAS

AF:

0.414

Gnomad FIN

AF:

0.545

Gnomad MID

AF:

0.649

Gnomad NFE

AF:

0.527

Gnomad OTH

AF:

0.531

GnomAD2 exomes

AF:

0.502

AC:

125596

AN:

250200

AF XY:

0.503

show subpopulations

Gnomad AFR exome

AF:

0.380

Gnomad AMR exome

AF:

0.518

Gnomad ASJ exome

AF:

0.613

Gnomad EAS exome

AF:

0.405

Gnomad FIN exome

AF:

0.536

Gnomad NFE exome

AF:

0.534

Gnomad OTH exome

AF:

0.553

GnomAD4 exome

AF:

0.514

AC:

751404

AN:

1461532

Hom.:

194703

Cov.:

AF XY:

0.513

AC XY:

372898

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.391

AC:

13084

AN:

33472

American (AMR)

AF:

0.522

AC:

23351

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.617

AC:

16130

AN:

26136

East Asian (EAS)

AF:

0.442

AC:

17532

AN:

39700

South Asian (SAS)

AF:

0.416

AC:

35866

AN:

86248

European-Finnish (FIN)

AF:

0.534

AC:

28436

AN:

53240

Middle Eastern (MID)

AF:

0.656

AC:

3774

AN:

5750

European-Non Finnish (NFE)

AF:

0.524

AC:

582180

AN:

1111896

Other (OTH)

AF:

0.514

AC:

31051

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

22058

44115

66173

88230

110288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16550

33100

49650

66200

82750

<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:

0.485

AC:

73861

AN:

152150

Hom.:

18350

Cov.:

AF XY:

0.485

AC XY:

36092

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.389

AC:

16141

AN:

41520

American (AMR)

AF:

0.525

AC:

8032

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.612

AC:

2122

AN:

3470

East Asian (EAS)

AF:

0.411

AC:

2123

AN:

5160

South Asian (SAS)

AF:

0.416

AC:

2005

AN:

4822

European-Finnish (FIN)

AF:

0.545

AC:

5764

AN:

10580

Middle Eastern (MID)

AF:

0.646

AC:

190

AN:

294

European-Non Finnish (NFE)

AF:

0.527

AC:

35852

AN:

67984

Other (OTH)

AF:

0.526

AC:

1111

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1936

3872

5807

7743

9679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

670

1340

2010

2680

3350

<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:

0.522

Hom.:

36677

Bravo

AF:

0.483

Asia WGS

AF:

0.415

AC:

1447

AN:

3478

EpiCase

AF:

0.538

EpiControl

AF:

0.557

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

Alzheimer disease 4

Benign:4

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 25, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dilated cardiomyopathy 1V

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.2

(source)

DANN

Benign

0.49

PhyloP100

-0.34

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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