chr1-226881992-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_000447.3(PSEN2):c.85C>T(p.Arg29Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000335 in 1,613,958 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000034 ( 1 hom. )
Consequence
PSEN2
NM_000447.3 missense
NM_000447.3 missense
Scores
3
10
6
Clinical Significance
Conservation
PhyloP100: 3.80
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_benign. Variant got -5 ACMG points.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000335 (49/1461746) while in subpopulation AMR AF= 0.000179 (8/44706). AF 95% confidence interval is 0.0000886. There are 1 homozygotes in gnomad4_exome. There are 25 alleles in male gnomad4_exome subpopulation. Median coverage is 67. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAd at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSEN2 | NM_000447.3 | c.85C>T | p.Arg29Cys | missense_variant | 4/13 | ENST00000366783.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSEN2 | ENST00000366783.8 | c.85C>T | p.Arg29Cys | missense_variant | 4/13 | 5 | NM_000447.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152212Hom.: 0 Cov.: 34
GnomAD3 genomes
?
AF:
AC:
5
AN:
152212
Hom.:
Cov.:
34
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251162Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135854
GnomAD3 exomes
AF:
AC:
5
AN:
251162
Hom.:
AF XY:
AC XY:
1
AN XY:
135854
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461746Hom.: 1 Cov.: 67 AF XY: 0.0000344 AC XY: 25AN XY: 727176
GnomAD4 exome
AF:
AC:
49
AN:
1461746
Hom.:
Cov.:
67
AF XY:
AC XY:
25
AN XY:
727176
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152212Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74364
GnomAD4 genome
?
AF:
AC:
5
AN:
152212
Hom.:
Cov.:
34
AF XY:
AC XY:
1
AN XY:
74364
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
1
ALSPAC
AF:
AC:
1
ESP6500AA
AF:
AC:
2
ESP6500EA
AF:
AC:
0
ExAC
?
AF:
AC:
3
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 07, 2022 | The c.85C>T (p.R29C) alteration is located in exon 4 (coding exon 1) of the PSEN2 gene. This alteration results from a C to T substitution at nucleotide position 85, causing the arginine (R) at amino acid position 29 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Alzheimer disease 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 29 of the PSEN2 protein (p.Arg29Cys). This variant is present in population databases (rs142892469, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with PSEN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1446296). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Alzheimer disease 4;C3150958:Dilated cardiomyopathy 1V Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 07, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
T;.;.;.;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;L;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;N;D;D;.
REVEL
Uncertain
Sift
Benign
T;T;T;D;.
Sift4G
Uncertain
T;T;T;D;D
Polyphen
D;.;.;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at