chr1-226881976-T-C

Position:

• chr1-226881976-T-C

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.69T>C​(p.Ala23=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.77 in 1,613,976 control chromosomes in the GnomAD database, including 479,454 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45659 hom., cov: 33)
  • Exomes 𝑓: 0.77 (433795 hom.)
• Consequence: PSEN2 NM_000447.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -2.55

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=-0.87).
• BP6: Variant 1-226881976-T-C is Benign according to our data. Variant chr1-226881976-T-C is described in ClinVar as [Benign]. Clinvar id is 256184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-226881976-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN2	NM_000447.3	c.69T>C	p.Ala23=	synonymous_variant	4/13	ENST00000366783.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN2	ENST00000366783.8	c.69T>C	p.Ala23=	synonymous_variant	4/13	5	NM_000447.3	P4

Frequencies

GnomAD3 genomes AF: 0.773 AC: 117509 AN: 152036 Hom.: 45619 Cov.: 33

Gnomad AFR AF: 0.816

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.766

Gnomad EAS AF: 0.571

Gnomad SAS AF: 0.744

Gnomad FIN AF: 0.789

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.772

Gnomad OTH AF: 0.756

GnomAD3 exomes AF: 0.756 AC: 190017 AN: 251334 Hom.: 72443 AF XY: 0.758 AC XY: 102966 AN XY: 135890

Gnomad AFR exome AF: 0.816

Gnomad AMR exome AF: 0.741

Gnomad ASJ exome AF: 0.757

Gnomad EAS exome AF: 0.554

Gnomad SAS exome AF: 0.754

Gnomad FIN exome AF: 0.786

Gnomad NFE exome AF: 0.778

Gnomad OTH exome AF: 0.778

GnomAD4 exome AF: 0.769 AC: 1124751 AN: 1461822 Hom.: 433795 Cov.: 72 AF XY: 0.769 AC XY: 559370 AN XY: 727212

Gnomad4 AFR exome AF: 0.827

Gnomad4 AMR exome AF: 0.745

Gnomad4 ASJ exome AF: 0.766

Gnomad4 EAS exome AF: 0.628

Gnomad4 SAS exome AF: 0.754

Gnomad4 FIN exome AF: 0.785

Gnomad4 NFE exome AF: 0.774

Gnomad4 OTH exome AF: 0.765

GnomAD4 genome AF: 0.773 AC: 117600 AN: 152154 Hom.: 45659 Cov.: 33 AF XY: 0.772 AC XY: 57415 AN XY: 74400

Gnomad4 AFR AF: 0.816

Gnomad4 AMR AF: 0.732

Gnomad4 ASJ AF: 0.766

Gnomad4 EAS AF: 0.571

Gnomad4 SAS AF: 0.744

Gnomad4 FIN AF: 0.789

Gnomad4 NFE AF: 0.772

Gnomad4 OTH AF: 0.756

Alfa AF: 0.772 Hom.: 89812

Bravo AF: 0.773

Asia WGS AF: 0.690 AC: 2400 AN: 3478

EpiCase AF: 0.771

EpiControl AF: 0.779

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 24, 2017	- -

Alzheimer disease 4 Benign:3

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2018	- -
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	- -

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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.028
DANN	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs11405; hg19: chr1-227069677; COSMIC: COSV60916086; COSMIC: COSV60916086;