rs143880787
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_001365999.1(SZT2):c.2812G>A(p.Ala938Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,613,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A938V) has been classified as Uncertain significance.
Frequency
Consequence
NM_001365999.1 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SZT2 | NM_001365999.1 | c.2812G>A | p.Ala938Thr | missense_variant, splice_region_variant | 19/72 | ENST00000634258.3 | |
SZT2 | NM_015284.4 | c.2812G>A | p.Ala938Thr | missense_variant, splice_region_variant | 19/71 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SZT2 | ENST00000634258.3 | c.2812G>A | p.Ala938Thr | missense_variant, splice_region_variant | 19/72 | 5 | NM_001365999.1 | P1 | |
SZT2 | ENST00000562955.2 | c.2812G>A | p.Ala938Thr | missense_variant, splice_region_variant | 19/71 | 5 | |||
SZT2 | ENST00000470139.1 | c.1543G>A | p.Ala515Thr | missense_variant, splice_region_variant, NMD_transcript_variant | 10/18 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000322 AC: 49AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000239 AC: 60AN: 251080Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135694
GnomAD4 exome AF: 0.000155 AC: 227AN: 1461544Hom.: 0 Cov.: 32 AF XY: 0.000171 AC XY: 124AN XY: 727042
GnomAD4 genome ? AF: 0.000322 AC: 49AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23AN XY: 74318
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 18 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jul 19, 2019 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP5. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 04, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 26, 2021 | Observed in a patient with childhood focal epilepsy with centro-temporal spikes through whole exome sequencing, however, a second SZT2 variant was not reported (Bobbili et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29358611) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 938 of the SZT2 protein (p.Ala938Thr). This variant is present in population databases (rs143880787, gnomAD 0.05%). This missense change has been observed in individual(s) with Rolandic epilepsy (PMID: 29358611). ClinVar contains an entry for this variant (Variation ID: 433087). 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. - |
Childhood epilepsy with centrotemporal spikes Pathogenic:1
Pathogenic, no assertion criteria provided | case-control | Bioinformatics Core, Luxembourg Center for Systems Biomedicine | Jan 01, 2017 | CAADphred>15 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at