rs201099906
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_001365999.1(SZT2):c.5906G>A(p.Arg1969Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,614,050 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 (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000050 ( 0 hom. )
Consequence
SZT2
NM_001365999.1 missense, splice_region
NM_001365999.1 missense, splice_region
Scores
5
4
7
Splicing: ADA: 0.9808
1
1
Clinical Significance
Conservation
PhyloP100: 9.63
Genes affected
SZT2 (HGNC:29040): (SZT2 subunit of KICSTOR complex) The protein encoded by this gene is expressed in the brain, predominantly in the parietal and frontal cortex as well as in dorsal root ganglia. It is localized to the peroxisome, and is implicated in resistance to oxidative stress. It likely functions by increasing superoxide dismutase (SOD) activity, but itself has no direct SOD activity. Studies in mice show that this gene confers low seizure threshold, and may also enhance epileptogenesis. [provided by RefSeq, Jun 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, SZT2
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SZT2 | NM_001365999.1 | c.5906G>A | p.Arg1969Gln | missense_variant, splice_region_variant | 42/72 | ENST00000634258.3 | |
SZT2 | NM_015284.4 | c.5735G>A | p.Arg1912Gln | missense_variant, splice_region_variant | 41/71 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SZT2 | ENST00000634258.3 | c.5906G>A | p.Arg1969Gln | missense_variant, splice_region_variant | 42/72 | 5 | NM_001365999.1 | P1 | |
SZT2 | ENST00000562955.2 | c.5735G>A | p.Arg1912Gln | missense_variant, splice_region_variant | 41/71 | 5 | |||
SZT2 | ENST00000648058.1 | n.2360G>A | splice_region_variant, non_coding_transcript_exon_variant | 10/40 | |||||
SZT2 | ENST00000649403.1 | n.656G>A | splice_region_variant, non_coding_transcript_exon_variant | 7/37 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152194Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000478 AC: 12AN: 251230Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135766
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GnomAD4 exome AF: 0.0000499 AC: 73AN: 1461738Hom.: 0 Cov.: 30 AF XY: 0.0000454 AC XY: 33AN XY: 727160
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74472
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 18 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1912 of the SZT2 protein (p.Arg1912Gln). This variant is present in population databases (rs201099906, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SZT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 411948). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
Sift4G
Pathogenic
D;D
Polyphen
1.0
.;D
Vest4
MVP
0.46
MPC
1.0
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at