rs28936380

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_000447.3(PSEN2):​c.365C>G​(p.Thr122Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T122P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

PSEN2
NM_000447.3 missense

Scores

14
4
1

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 7.67
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-226885545-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 1-226885546-C-G is Pathogenic according to our data. Variant chr1-226885546-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 8851.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226885546-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PSEN2NM_000447.3 linkuse as main transcriptc.365C>G p.Thr122Arg missense_variant 6/13 ENST00000366783.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PSEN2ENST00000366783.8 linkuse as main transcriptc.365C>G p.Thr122Arg missense_variant 6/135 NM_000447.3 P4P49810-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Alzheimer disease 4 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2003- -
not provided Other:1
not provided, no classification providedliterature onlyVIB Department of Molecular Genetics, University of Antwerp-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
D;.;.;.;.
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D;D;D;.;D
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
2.9
M;.;M;.;.
MutationTaster
Benign
1.0
A;A;A;A;A;A
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-5.4
D;D;D;D;.
REVEL
Pathogenic
0.96
Sift
Uncertain
0.0010
D;D;D;D;.
Sift4G
Uncertain
0.0050
D;D;D;D;D
Polyphen
0.99
D;.;.;.;.
Vest4
0.97
MutPred
0.95
Gain of phosphorylation at T125 (P = 0.0823);Gain of phosphorylation at T125 (P = 0.0823);Gain of phosphorylation at T125 (P = 0.0823);.;.;
MVP
0.99
MPC
0.91
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.91
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.31
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.31
Position offset: 1

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: rs28936380; hg19: chr1-227073247; API