1-226882036-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000447.3(PSEN2):c.129C>T(p.Asn43=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.345

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]

ACMG classification

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	UniProt
PSEN2	NM_000447.3	c.129C>T	p.Asn43=	synonymous_variant	4/13	ENST00000366783.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN2	ENST00000366783.8	c.129C>T	p.Asn43=	synonymous_variant	4/13	5	NM_000447.3	P4

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73822 AN: 152032 Hom.: 18340 Cov.: 33

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

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.: 66 AF XY: 0.513 AC XY: 372898 AN XY: 727076

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.: 33 AF XY: 0.485 AC XY: 36092 AN XY: 74370

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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Alzheimer disease 4 Benign:4

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. -
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	Invitae	Feb 01, 2024	- -

Dilated cardiomyopathy 1V Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

not provided Benign:2

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	- -

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

Other links and lift over

dbSNP: rs6759; hg19: chr1-227069737; COSMIC: COSV60915273; COSMIC: COSV60915273;