rs139972151
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2
The NM_000447.3(PSEN2):c.208G>A(p.Gly70Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000447.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSEN2 | NM_000447.3 | c.208G>A | p.Gly70Arg | missense_variant | 5/13 | ENST00000366783.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSEN2 | ENST00000366783.8 | c.208G>A | p.Gly70Arg | missense_variant | 5/13 | 5 | NM_000447.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251294Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135858
GnomAD4 exome AF: 0.0000458 AC: 67AN: 1461866Hom.: 0 Cov.: 43 AF XY: 0.0000440 AC XY: 32AN XY: 727222
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74362
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PSEN2 p.Gly70Arg variant was identified in 1 of 454 proband chromosomes (frequency: 0.0022) from a cohort of 227 unrelated probands clinically diagnosed for Alzheimer disease with symptoms occuring before 70 years old (Wojtas_2012_PMID:23383383). The variant was identified in dbSNP (ID: rs139972151) and ClinVar (classified as likely benign by Biesecker Lab). The variant was identified in control databases in 17 of 282688 chromosomes at a frequency of 0.00006014 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 14 of 129028 chromosomes (freq: 0.000109), Latino in 2 of 35436 chromosomes (freq: 0.000056) and South Asian in 1 of 30616 chromosomes (freq: 0.000033), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. The p.Gly70 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 29, 2021 | The PSEN2 c.208G>A; p.Gly70Arg variant (rs139972151) has been described in at least two individuals who had a clinical diagnosis of Alzheimer’s disease, but no additional clinical information was available (Wojtas 2012, see link to Alzheimer’s Association International Conference (AAIC) 2019 abstract). This variant contains an entry in ClinVar (Variation ID: 192129), and is found in the non-Finnish European population with an allele frequency of 0.011% (14/129028 alleles) in the Genome Aggregation Database. The glycine at codon 70 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.456). However, given the lack of clinical and functional data, the significance of the p.Gly70Arg variant is uncertain at this time. REFERENCES Wojtas A et al. C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic. Am J Neurodegener Dis. 2012;1(1):107-18. PMID: 23383383. Link to AAIC 2019 P3-120 abstract: https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1016/j.jalz.2019.06.3148 - |
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
PSEN2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 26, 2023 | The PSEN2 c.208G>A variant is predicted to result in the amino acid substitution p.Gly70Arg. This variant was reported in a patient with early-onset Alzheimer's disease (Wojtas et al. 2012. PubMed ID: 23383383) and as a likely benign variant in a study of patients with coronary artery disease risk (Ng et al. 2013. PubMed ID: 23861362). It is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Alzheimer disease 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 26, 2021 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with Alzheimer disease (PMID: 23383383). ClinVar contains an entry for this variant (Variation ID: 192129). This variant is present in population databases (rs139972151, ExAC 0.009%). This sequence change replaces glycine with arginine at codon 70 of the PSEN2 protein (p.Gly70Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at