1-226888522-C-G

Position:

• chr1-226888522-C-G

Variant summary

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

The NM_000447.3(PSEN2):​c.567-307C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 152,158 control chromosomes in the GnomAD database, including 3,314 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 0.20 (3314 hom., cov: 32)
• Consequence: PSEN2 NM_000447.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.400

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN2	NM_000447.3	c.567-307C>G		intron_variant		ENST00000366783.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN2	ENST00000366783.8	c.567-307C>G		intron_variant		5	NM_000447.3	P4

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30770 AN: 152040 Hom.: 3311 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.162

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

GnomAD4 genome AF: 0.202 AC: 30791 AN: 152158 Hom.: 3314 Cov.: 32 AF XY: 0.202 AC XY: 15015 AN XY: 74380

Gnomad4 AFR AF: 0.169

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.267

Gnomad4 FIN AF: 0.239

Gnomad4 NFE AF: 0.238

Gnomad4 OTH AF: 0.168

Alfa AF: 0.115 Hom.: 201

Bravo AF: 0.194

Asia WGS AF: 0.216 AC: 748 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.6
DANN	Benign	0.80

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: rs1800681; hg19: chr1-227076223;