1-226871336-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000447.3(PSEN2):c.-275C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 152,224 control chromosomes in the GnomAD database, including 2,289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.16 ( 2287 hom., cov: 32)

Exomes 𝑓: 0.19 ( 2 hom. )

Consequence

PSEN2
NM_000447.3 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.467

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 1-226871336-C-T is Benign according to our data. Variant chr1-226871336-C-T is described in ClinVar as [Benign]. Clinvar id is 295983.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-226871336-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN2	NM_000447.3 linkuse as main transcript	c.-275C>T		5_prime_UTR_variant	2/13	ENST00000366783.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN2	ENST00000366783.8 linkuse as main transcript	c.-275C>T		5_prime_UTR_variant	2/13	5	NM_000447.3	P4	P49810-1

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23819

AN:

152034

Hom.:

2285

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0448

Gnomad AMI

AF:

0.254

Gnomad AMR

AF:

0.186

Gnomad ASJ

AF:

0.204

Gnomad EAS

AF:

0.249

Gnomad SAS

AF:

0.173

Gnomad FIN

AF:

0.147

Gnomad MID

AF:

0.162

Gnomad NFE

AF:

0.207

Gnomad OTH

AF:

0.174

GnomAD4 exome

AF:

0.194

AC:

AN:

Hom.:

Cov.:

AF XY:

0.217

AC XY:

AN XY:

show subpopulations

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.250

Gnomad4 EAS exome

AF:

0.500

Gnomad4 FIN exome

AF:

0.167

Gnomad4 NFE exome

AF:

0.212

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.157

AC:

23818

AN:

152152

Hom.:

2287

Cov.:

AF XY:

0.156

AC XY:

11607

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0448

Gnomad4 AMR

AF:

0.186

Gnomad4 ASJ

AF:

0.204

Gnomad4 EAS

AF:

0.248

Gnomad4 SAS

AF:

0.173

Gnomad4 FIN

AF:

0.147

Gnomad4 NFE

AF:

0.207

Gnomad4 OTH

AF:

0.174

Alfa

AF:

0.195

Hom.:

2919

Bravo

AF:

0.149

Asia WGS

AF:

0.183

AC:

639

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1V

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Alzheimer disease 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

Cadd

Benign

9.7

Dann

Benign

0.58

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over