1-226882036-C-T

Position:

chr1-226882036-C-T

Variant summary

Our verdict is Benign. Variant got -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

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:

ENSG00000288674 (HGNC:):

ENSG00000288674 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 256180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-226882036-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
PSEN2	NM_000447.3 linkuse as main transcript	c.129C>T	p.Asn43Asn	synonymous_variant	4/13	ENST00000366783.8	NP_000438.2	P49810-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSEN2	ENST00000366783.8 linkuse as main transcript	c.129C>T	p.Asn43Asn	synonymous_variant	4/13	5	NM_000447.3	ENSP00000355747.3		P49810-1
ENSG00000288674	ENST00000366779.6 linkuse as main transcript	n.129C>T		non_coding_transcript_exon_variant	4/32	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

GnomAD3 exomes

AF:

0.502

AC:

125596

AN:

250200

Hom.:

32209

AF XY:

0.503

AC XY:

68082

AN XY:

135448

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 SAS exome

AF:

0.418

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

Gnomad4 AFR exome

AF:

0.391

Gnomad4 AMR exome

AF:

0.522

Gnomad4 ASJ exome

AF:

0.617

Gnomad4 EAS exome

AF:

0.442

Gnomad4 SAS exome

AF:

0.416

Gnomad4 FIN exome

AF:

0.534

Gnomad4 NFE exome

AF:

0.524

Gnomad4 OTH exome

AF:

0.514

GnomAD4 genome

AF:

0.485

AC:

73861

AN:

152150

Hom.:

18350

Cov.:

AF XY:

0.485

AC XY:

36092

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.389

Gnomad4 AMR

AF:

0.525

Gnomad4 ASJ

AF:

0.612

Gnomad4 EAS

AF:

0.411

Gnomad4 SAS

AF:

0.416

Gnomad4 FIN

AF:

0.545

Gnomad4 NFE

AF:

0.527

Gnomad4 OTH

AF:

0.526

Alfa

AF:

0.529

Hom.:

28179

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

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Alzheimer disease 4

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2018	- -

Dilated cardiomyopathy 1V

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.2

DANN

Benign

0.49

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

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