1-226888972-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PP3_ModerateBS1_SupportingBS2
The NM_000447.3(PSEN2):c.710C>T(p.Ala237Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,614,026 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A237A) has been classified as Likely benign.
Frequency
Consequence
NM_000447.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PSEN2 | ENST00000366783.8 | c.710C>T | p.Ala237Val | missense_variant | Exon 8 of 13 | 5 | NM_000447.3 | ENSP00000355747.3 | ||
ENSG00000288674 | ENST00000366779.6 | n.710C>T | non_coding_transcript_exon_variant | Exon 8 of 32 | 2 | ENSP00000355741.2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251378Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135882
GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727244
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74320
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: PSEN2 c.710C>T (p.Ala237Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251378 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PSEN2 causing Alzheimer Disease 4, allowing no conclusion about variant significance. c.710C>T has been reported in the literature in individuals affected with Alzheimer Disease (Sassi_2014). The report does not provide unequivocal conclusions about association of the variant with Alzheimer Disease 4. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30279455, 25104557). ClinVar contains an entry for this variant (Variation ID: 191772). Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at