1-226883768-C-G
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_000447.3(PSEN2):c.205C>G(p.Pro69Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P69P) has been classified as Likely benign.
Frequency
Consequence
NM_000447.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSEN2 | NM_000447.3 | c.205C>G | p.Pro69Ala | missense_variant | 5/13 | ENST00000366783.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSEN2 | ENST00000366783.8 | c.205C>G | p.Pro69Ala | missense_variant | 5/13 | 5 | NM_000447.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152128Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251264Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135866
GnomAD4 exome AF: 0.0000575 AC: 84AN: 1461838Hom.: 0 Cov.: 44 AF XY: 0.0000536 AC XY: 39AN XY: 727216
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152128Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74302
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2021 | - - |
Alzheimer disease 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2023 | This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 69 of the PSEN2 protein (p.Pro69Ala). This variant is present in population databases (rs202133351, gnomAD 0.02%). This missense change has been observed in individual(s) with Alzheimer disease (PMID: 22221884). ClinVar contains an entry for this variant (Variation ID: 191771). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect PSEN2 function (PMID: 32087291). 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 | Oct 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at