1-43428384-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_001365999.1(SZT2):ā€‹c.4064A>Gā€‹(p.His1355Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00020 ( 0 hom., cov: 32)
Exomes š‘“: 0.000015 ( 0 hom. )

Consequence

SZT2
NM_001365999.1 missense

Scores

4
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 1.42
Variant links:
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 Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SZT2. . Gene score misZ 2.5968 (greater than the threshold 3.09). Trascript score misZ 4.0086 (greater than threshold 3.09). GenCC has associacion of gene with undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy, 18, developmental and epileptic encephalopathy.
BP4
Computational evidence support a benign effect (MetaRNN=0.039798737).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SZT2NM_001365999.1 linkuse as main transcriptc.4064A>G p.His1355Arg missense_variant 28/72 ENST00000634258.3 NP_001352928.1
SZT2NM_015284.4 linkuse as main transcriptc.3893A>G p.His1298Arg missense_variant 27/71 NP_056099.3 Q5T011-5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SZT2ENST00000634258.3 linkuse as main transcriptc.4064A>G p.His1355Arg missense_variant 28/725 NM_001365999.1 ENSP00000489255.1 Q5T011-1
SZT2ENST00000562955.2 linkuse as main transcriptc.3893A>G p.His1298Arg missense_variant 27/715 ENSP00000457168.1 Q5T011-5
SZT2ENST00000470139.1 linkuse as main transcriptn.*1199A>G non_coding_transcript_exon_variant 18/182 ENSP00000492726.1 A0A1W2PRY5
SZT2ENST00000470139.1 linkuse as main transcriptn.*1199A>G 3_prime_UTR_variant 18/182 ENSP00000492726.1 A0A1W2PRY5

Frequencies

GnomAD3 genomes
AF:
0.000197
AC:
30
AN:
152132
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000676
AC:
17
AN:
251494
Hom.:
0
AF XY:
0.0000441
AC XY:
6
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.000923
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000150
AC:
22
AN:
1461894
Hom.:
0
Cov.:
32
AF XY:
0.00000963
AC XY:
7
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.000568
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.000197
AC:
30
AN:
152250
Hom.:
0
Cov.:
32
AF XY:
0.000188
AC XY:
14
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.000722
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000444
Hom.:
0
Bravo
AF:
0.000264
ESP6500AA
AF:
0.00136
AC:
6
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000988
AC:
12

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 18 Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityDec 31, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 13, 2022This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1298 of the SZT2 protein (p.His1298Arg). This variant is present in population databases (rs149741610, gnomAD 0.08%). 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: 411937). 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 not expected to disrupt SZT2 protein function. 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. -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicNov 25, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxOct 23, 2024In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 25, 2024The c.3893A>G (p.H1298R) alteration is located in exon 27 (coding exon 27) of the SZT2 gene. This alteration results from a A to G substitution at nucleotide position 3893, causing the histidine (H) at amino acid position 1298 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Benign
0.082
T;.
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.084
FATHMM_MKL
Benign
0.46
N
LIST_S2
Benign
0.72
T;T
M_CAP
Benign
0.0014
T
MetaRNN
Benign
0.040
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.0
L;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-1.5
.;N
Sift
Uncertain
0.022
.;D
Sift4G
Uncertain
0.037
D;D
Polyphen
0.0
.;B
Vest4
0.31
MVP
0.42
MPC
0.32
ClinPred
0.035
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.052
gMVP
0.17

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs149741610; hg19: chr1-43894055; API