rs2802268

Positions:

• chr1-226896959-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000366779.6(ENSG00000288674):​n.*1380T>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 152,094 control chromosomes in the GnomAD database, including 4,810 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 0.25 (4810 hom., cov: 32)
• Consequence: ENSG00000288674 ENST00000366779.6 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.599

Genes affected

ENSG00000288674 (HGNC:):

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSEN2	XR_001737316.3	n.1456-761T>G		intron_variant
PSEN2	XR_007061979.1	n.1456-761T>G		intron_variant
PSEN2	XR_007061980.1	n.1456-761T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000288674	ENST00000366779.6	n.*1380T>G		non_coding_transcript_exon_variant	13/32	2		ENSP00000355741.2
ENSG00000288674	ENST00000366779.6	n.*1380T>G		3_prime_UTR_variant	13/32	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37423 AN: 151976 Hom.: 4798 Cov.: 32

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.276

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

GnomAD4 genome AF: 0.246 AC: 37456 AN: 152094 Hom.: 4810 Cov.: 32 AF XY: 0.250 AC XY: 18558 AN XY: 74344

Gnomad4 AFR AF: 0.238

Gnomad4 AMR AF: 0.319

Gnomad4 ASJ AF: 0.303

Gnomad4 EAS AF: 0.399

Gnomad4 SAS AF: 0.209

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.222

Gnomad4 OTH AF: 0.273

Alfa AF: 0.238 Hom.: 6155

Bravo AF: 0.255

Asia WGS AF: 0.307 AC: 1071 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.4
DANN	Benign	0.37

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2802268; hg19: chr1-227084660; COSMIC: COSV60915367;