rs2802268

Variant names:

• chr1-226896959-T-G
• rs2802268
• ENST00000366779.6:n.*1380T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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]

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

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000366779.6. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000288674	ENST00000366779.6	TSL:2	n.*1380T>G		non_coding_transcript_exon	Exon 13 of 32	ENSP00000355741.2
	ENSG00000288674	ENST00000366779.6	TSL:2	n.*1380T>G		3_prime_UTR	Exon 13 of 32	ENSP00000355741.2
	PSEN2	ENST00000900065.1		c.*1380T>G		3_prime_UTR	Exon 12 of 12	ENSP00000570124.1

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

African (AFR) AF: 0.238 AC: 9885 AN: 41504

American (AMR) AF: 0.319 AC: 4870 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1051 AN: 3470

East Asian (EAS) AF: 0.399 AC: 2056 AN: 5156

South Asian (SAS) AF: 0.209 AC: 1006 AN: 4814

European-Finnish (FIN) AF: 0.249 AC: 2636 AN: 10582

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.222 AC: 15104 AN: 67978

Other (OTH) AF: 0.273 AC: 577 AN: 2112

Alfa AF: 0.238 Hom.: 13696

Bravo AF: 0.255

Asia WGS AF: 0.307 AC: 1071 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.4
DANN	Benign	0.37
PhyloP100		0.60

Splicing

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

Other links and lift over

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