rs1295640

Variant names:

• chr1-226882677-C-T
• rs1295640
• NM_000447.3:c.141+629C>T

Variant summary

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

The NM_000447.3(PSEN2):​c.141+629C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.486 in 151,910 control chromosomes in the GnomAD database, including 18,308 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 0.49 (18308 hom., cov: 32)
• Consequence: PSEN2 NM_000447.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.217
• Publications: 9 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000447.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSEN2	NM_000447.3	MANE Select	c.141+629C>T		intron	N/A	NP_000438.2
	PSEN2	NM_001437537.1		c.141+629C>T		intron	N/A	NP_001424466.1
	PSEN2	NM_012486.3		c.141+629C>T		intron	N/A	NP_036618.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSEN2	ENST00000366783.8	TSL:5 MANE Select	c.141+629C>T		intron	N/A	ENSP00000355747.3
	PSEN2	ENST00000366782.6	TSL:1	c.141+629C>T		intron	N/A	ENSP00000355746.2
	ENSG00000288674	ENST00000366779.6	TSL:2	n.141+629C>T		intron	N/A	ENSP00000355741.2

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73718 AN: 151792 Hom.: 18298 Cov.: 32

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: 0.546

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.531

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

GnomAD4 genome AF: 0.486 AC: 73757 AN: 151910 Hom.: 18308 Cov.: 32 AF XY: 0.485 AC XY: 36038 AN XY: 74244

African (AFR) AF: 0.389 AC: 16101 AN: 41406

American (AMR) AF: 0.525 AC: 8026 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 2124 AN: 3472

East Asian (EAS) AF: 0.411 AC: 2122 AN: 5160

South Asian (SAS) AF: 0.416 AC: 2005 AN: 4820

European-Finnish (FIN) AF: 0.546 AC: 5742 AN: 10526

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.527 AC: 35815 AN: 67928

Other (OTH) AF: 0.527 AC: 1111 AN: 2110

Alfa AF: 0.517 Hom.: 63427

Bravo AF: 0.483

Asia WGS AF: 0.415 AC: 1447 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.9
DANN	Benign	0.84
PhyloP100		-0.22
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: rs1295640; hg19: chr1-227070378;