rs148996705

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000447.3(PSEN2):​c.366G>A​(p.Thr122Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,613,948 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

PSEN2
NM_000447.3 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.65
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.5).
BP6
Variant 1-226885547-G-A is Benign according to our data. Variant chr1-226885547-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-226885547-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-2.65 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000913 (139/152216) while in subpopulation NFE AF= 0.00181 (123/68004). AF 95% confidence interval is 0.00155. There are 0 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 139 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PSEN2NM_000447.3 linkuse as main transcriptc.366G>A p.Thr122Thr synonymous_variant 6/13 ENST00000366783.8 NP_000438.2 P49810-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PSEN2ENST00000366783.8 linkuse as main transcriptc.366G>A p.Thr122Thr synonymous_variant 6/135 NM_000447.3 ENSP00000355747.3 P49810-1
ENSG00000288674ENST00000366779.6 linkuse as main transcriptn.366G>A non_coding_transcript_exon_variant 6/322 ENSP00000355741.2

Frequencies

GnomAD3 genomes
AF:
0.000914
AC:
139
AN:
152098
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00181
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00102
AC:
256
AN:
250886
Hom.:
0
AF XY:
0.00108
AC XY:
147
AN XY:
135614
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.0000994
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000458
Gnomad FIN exome
AF:
0.00167
Gnomad NFE exome
AF:
0.00167
Gnomad OTH exome
AF:
0.00147
GnomAD4 exome
AF:
0.00115
AC:
1685
AN:
1461732
Hom.:
4
Cov.:
31
AF XY:
0.00115
AC XY:
838
AN XY:
727144
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000464
Gnomad4 FIN exome
AF:
0.00225
Gnomad4 NFE exome
AF:
0.00130
Gnomad4 OTH exome
AF:
0.00103
GnomAD4 genome
AF:
0.000913
AC:
139
AN:
152216
Hom.:
0
Cov.:
31
AF XY:
0.000753
AC XY:
56
AN XY:
74400
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000943
Gnomad4 NFE
AF:
0.00181
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00144
Hom.:
0
Bravo
AF:
0.000718
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00191
EpiControl
AF:
0.00166

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2023PSEN2: BP4, BP7, BS1 -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Alzheimer disease 4 Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Dilated cardiomyopathy 1V Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.50
CADD
Benign
3.2
DANN
Benign
0.79

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.

Other links and lift over

dbSNP: rs148996705; hg19: chr1-227073248; API