Genetic Variant NM_001365999.1:c.8803C>T (chr1-43443774-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001365999.1(SZT2):c.8803C>T(p.Arg2935Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,438 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R2935Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SZT2
NM_001365999.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 4.37

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]

SZT2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SZT2	NM_001365999.1 link	c.8803C>T	p.Arg2935Trp	missense_variant	Exon 62 of 72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4 link	c.8632C>T	p.Arg2878Trp	missense_variant	Exon 61 of 71		NP_056099.3	Q5T011-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3 link	c.8803C>T	p.Arg2935Trp	missense_variant	Exon 62 of 72	5	NM_001365999.1	ENSP00000489255.1		Q5T011-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461438

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Self-limited epilepsy with centrotemporal spikes

Pathogenic:1

Jan 01, 2017

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

CAADphred>15 -

not provided

Uncertain:1

Apr 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 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. ClinVar contains an entry for this variant (Variation ID: 433095). This missense change has been observed in individual(s) with clinical features of SZT2-related conditions (PMID: 29358611). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2878 of the SZT2 protein (p.Arg2878Trp). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.9

L;.

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.5

.;D

Sift

Uncertain

0.0020

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.70

MutPred

0.45

.;Loss of disorder (P = 0.0091);

MVP

0.44

MPC

0.95

ClinPred

1.0

GERP RS

4.4

Varity_R

0.53

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over