rs367855127
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PP3_ModerateBS1_SupportingBS2
The NM_000447.3(PSEN2):c.712C>T(p.Leu238Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000421 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L238P) has been classified as Uncertain significance.
Frequency
Consequence
NM_000447.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSEN2 | NM_000447.3 | c.712C>T | p.Leu238Phe | missense_variant | 8/13 | ENST00000366783.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSEN2 | ENST00000366783.8 | c.712C>T | p.Leu238Phe | missense_variant | 8/13 | 5 | NM_000447.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251382Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135882
GnomAD4 exome AF: 0.0000445 AC: 65AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 31AN XY: 727246
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74340
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 08, 2022 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features of Alzheimer disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. When expressed in a cell line lacking endogenous PSEN2, this variant resulted in an increase in the ratio of amyloid beta-42 to -40 (PMID: 32087291). - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 05, 2020 | Previously reported as a variant of uncertain significance or possible risk factor for Alzheimer's disease with conflicting interpretations of pathogenicity (Hsu et al., 2018; Hsu et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26522186, 25937274, 30021643, 30045758, 32087291) - |
Alzheimer disease 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 238 of the PSEN2 protein (p.Leu238Phe). This variant is present in population databases (rs367855127, gnomAD 0.004%). This missense change has been observed in individual(s) with Alzheimer's disease (PMID: 25937274, 30021643). ClinVar contains an entry for this variant (Variation ID: 448151). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PSEN2 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PSEN2 function (PMID: 30021643, 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 | Jul 14, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at