1-226875528-C-T

Position:

• chr1-226875528-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000447.3(PSEN2):​c.-43C>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 0.077 in 152,188 control chromosomes in the GnomAD database, including 1,198 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.077 (1198 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PSEN2 NM_000447.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.271

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-226875528-C-T is Benign according to our data. Variant chr1-226875528-C-T is described in ClinVar as [Benign]. Clinvar id is 295986.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN2	NM_000447.3	c.-43C>T		5_prime_UTR_variant	3/13	ENST00000366783.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN2	ENST00000366783.8	c.-43C>T		5_prime_UTR_variant	3/13	5	NM_000447.3	P4

Frequencies

GnomAD3 genomes AF: 0.0768 AC: 11684 AN: 152072 Hom.: 1194 Cov.: 32

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0550

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.0567

Gnomad SAS AF: 0.0588

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.0635

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 28 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 22

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0770 AC: 11721 AN: 152188 Hom.: 1198 Cov.: 32 AF XY: 0.0763 AC XY: 5674 AN XY: 74402

Gnomad4 AFR AF: 0.236

Gnomad4 AMR AF: 0.0548

Gnomad4 ASJ AF: 0.0349

Gnomad4 EAS AF: 0.0570

Gnomad4 SAS AF: 0.0591

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.00309

Gnomad4 OTH AF: 0.0629

Alfa AF: 0.0148 Hom.: 186

Bravo AF: 0.0878

Asia WGS AF: 0.0610 AC: 212 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1V Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs7961; hg19: chr1-227063229;