chr1-226870643-A-G

Position:

• chr1-226870643-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000447.3(PSEN2):​c.-356A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 151,934 control chromosomes in the GnomAD database, including 19,419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19394 hom., cov: 34)
  • Exomes 𝑓: 0.44 (25 hom.)
• Consequence: PSEN2 NM_000447.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.204

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-226870643-A-G is Benign according to our data. Variant chr1-226870643-A-G is described in ClinVar as [Benign]. Clinvar id is 295980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-226870643-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSEN2	NM_000447.3	c.-356A>G		5_prime_UTR_variant	1/13	ENST00000366783.8	NP_000438.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSEN2	ENST00000366783.8	c.-356A>G		5_prime_UTR_variant	1/13	5	NM_000447.3	ENSP00000355747	P4

Frequencies

GnomAD3 genomes AF: 0.502 AC: 75995 AN: 151524 Hom.: 19373 Cov.: 34

Gnomad AFR AF: 0.572

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.583

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.350

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.463

GnomAD4 exome AF: 0.440 AC: 133 AN: 302 Hom.: 25 Cov.: 0 AF XY: 0.440 AC XY: 102 AN XY: 232

Gnomad4 AFR exome AF: 0.833

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.375

Gnomad4 SAS exome AF: 0.750

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.430

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.502 AC: 76055 AN: 151632 Hom.: 19394 Cov.: 34 AF XY: 0.502 AC XY: 37215 AN XY: 74126

Gnomad4 AFR AF: 0.572

Gnomad4 AMR AF: 0.452

Gnomad4 ASJ AF: 0.407

Gnomad4 EAS AF: 0.583

Gnomad4 SAS AF: 0.584

Gnomad4 FIN AF: 0.451

Gnomad4 NFE AF: 0.473

Gnomad4 OTH AF: 0.467

Alfa AF: 0.341 Hom.: 859

Bravo AF: 0.500

Asia WGS AF: 0.567 AC: 1876 AN: 3316

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	14
DANN	Benign	0.53

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

Other links and lift over

dbSNP: rs12758915; hg19: chr1-227058344;