NM_000447.3:c.498+745G>A

Variant names:

• chr1-226886424-G-A
• rs2236913
• NM_000447.3:c.498+745G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000447.3(PSEN2):​c.498+745G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.692 in 152,054 control chromosomes in the GnomAD database, including 37,105 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.69 (37105 hom., cov: 32)
• Consequence: PSEN2 NM_000447.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.48
• Publications: 6 publications found

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

ENSG00000288674 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSEN2	NM_000447.3	c.498+745G>A		intron_variant	Intron 6 of 12	ENST00000366783.8	NP_000438.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSEN2	ENST00000366783.8	c.498+745G>A		intron_variant	Intron 6 of 12	5	NM_000447.3	ENSP00000355747.3
ENSG00000288674	ENST00000366779.6	n.498+745G>A		intron_variant	Intron 6 of 31	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes AF: 0.692 AC: 105181 AN: 151936 Hom.: 37088 Cov.: 32

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.676

Gnomad ASJ AF: 0.732

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.769

Gnomad OTH AF: 0.690

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.692 AC: 105233 AN: 152054 Hom.: 37105 Cov.: 32 AF XY: 0.692 AC XY: 51431 AN XY: 74334

African (AFR) AF: 0.566 AC: 23455 AN: 41430

American (AMR) AF: 0.676 AC: 10340 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.732 AC: 2540 AN: 3472

East Asian (EAS) AF: 0.513 AC: 2643 AN: 5152

South Asian (SAS) AF: 0.685 AC: 3302 AN: 4820

European-Finnish (FIN) AF: 0.788 AC: 8333 AN: 10570

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.769 AC: 52256 AN: 67996

Other (OTH) AF: 0.691 AC: 1461 AN: 2114

Alfa AF: 0.728 Hom.: 15897

Bravo AF: 0.680

Asia WGS AF: 0.628 AC: 2185 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.27
DANN	Benign	0.53
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2236913; hg19: chr1-227074125;