1-43431066-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001365999.1(SZT2):c.4892C>T(p.Thr1631Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,613,896 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1631T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 2 hom. )

Consequence

SZT2
NM_001365999.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 3.10

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 18
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Illumina
genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SZT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007987797).

BP6

Variant 1-43431066-C-T is Benign according to our data. Variant chr1-43431066-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 411931.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SZT2	NM_001365999.1 link	c.4892C>T	p.Thr1631Met	missense_variant	Exon 33 of 72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4 link	c.4721C>T	p.Thr1574Met	missense_variant	Exon 32 of 71		NP_056099.3	Q5T011-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SZT2	ENST00000634258.3 link	c.4892C>T	p.Thr1631Met	missense_variant	Exon 33 of 72	5	NM_001365999.1	ENSP00000489255.1	Q5T011-1
SZT2	ENST00000562955.2 link	c.4721C>T	p.Thr1574Met	missense_variant	Exon 32 of 71	5		ENSP00000457168.1	Q5T011-5
SZT2	ENST00000648058.1 link	n.32C>T		non_coding_transcript_exon_variant	Exon 1 of 40
SZT2	ENST00000638642.1 link	n.-65C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000442

AC:

111

AN:

251138

AF XY:

0.000516

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000242

AC:

354

AN:

1461664

Hom.:

Cov.:

AF XY:

0.000314

AC XY:

228

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33476

American (AMR)

AF:

0.0000224

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00209

AC:

180

AN:

86216

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000118

AC:

131

AN:

1111920

Other (OTH)

AF:

0.000381

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000145

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41534

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00166

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.000404

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 18

Uncertain:2

Jun 16, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SZT2 NM_015284.3 exon 32 p.Thr1574Met (c.4721C>T): This variant has not been reported in the literature but is present in 0.01% (11/68026) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-43431066-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:411931). This variant amino acid Methionine (Met) is present in >10 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jun 06, 2019

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T1574M variant (also known as c.4721C>T), located in coding exon 32 of the SZT2 gene, results from a C to T substitution at nucleotide position 4721. The threonine at codon 1574 is replaced by methionine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

SZT2-related disorder

Benign:1

Apr 01, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.034

T;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.0026

MetaRNN

Benign

0.0080

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;.

PhyloP100

3.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.16

.;N

Sift

Benign

0.12

.;T

Sift4G

Benign

0.13

T;T

Polyphen

0.0030

.;B

Vest4

0.20

MVP

0.17

MPC

0.37

ClinPred

0.013

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.028

gMVP

0.32

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over