rs2255632

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001365999.1(SZT2):c.8626-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,613,750 control chromosomes in the GnomAD database, including 126,714 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 9089 hom., cov: 32)

Exomes 𝑓: 0.39 ( 117625 hom. )

Consequence

SZT2
NM_001365999.1 splice_region, intron

Scores

Splicing: ADA: 0.00003135

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.92

Publications

25 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 1-43443594-T-C is Benign according to our data. Variant chr1-43443594-T-C is described in ClinVar as Benign. ClinVar VariationId is 260626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SZT2	NM_001365999.1 link	c.8626-3T>C		splice_region_variant, intron_variant	Intron 61 of 71	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4 link	c.8455-3T>C		splice_region_variant, intron_variant	Intron 60 of 70		NP_056099.3	Q5T011-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3 link	c.8626-3T>C		splice_region_variant, intron_variant	Intron 61 of 71	5	NM_001365999.1	ENSP00000489255.1		Q5T011-1

Frequencies

GnomAD3 genomes

AF:

0.322

AC:

48915

AN:

151952

Hom.:

9090

Cov.:

show subpopulations

Gnomad AFR

AF:

0.147

Gnomad AMI

AF:

0.480

Gnomad AMR

AF:

0.392

Gnomad ASJ

AF:

0.465

Gnomad EAS

AF:

0.124

Gnomad SAS

AF:

0.158

Gnomad FIN

AF:

0.407

Gnomad MID

AF:

0.456

Gnomad NFE

AF:

0.414

Gnomad OTH

AF:

0.382

GnomAD2 exomes

AF:

0.337

AC:

84632

AN:

251052

AF XY:

0.337

show subpopulations

Gnomad AFR exome

AF:

0.139

Gnomad AMR exome

AF:

0.330

Gnomad ASJ exome

AF:

0.471

Gnomad EAS exome

AF:

0.112

Gnomad FIN exome

AF:

0.411

Gnomad NFE exome

AF:

0.422

Gnomad OTH exome

AF:

0.381

GnomAD4 exome

AF:

0.391

AC:

571782

AN:

1461680

Hom.:

117625

Cov.:

AF XY:

0.386

AC XY:

280696

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.135

AC:

4526

AN:

33480

American (AMR)

AF:

0.340

AC:

15215

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.468

AC:

12242

AN:

26136

East Asian (EAS)

AF:

0.158

AC:

6290

AN:

39700

South Asian (SAS)

AF:

0.169

AC:

14605

AN:

86258

European-Finnish (FIN)

AF:

0.404

AC:

21514

AN:

53274

Middle Eastern (MID)

AF:

0.423

AC:

2438

AN:

5768

European-Non Finnish (NFE)

AF:

0.425

AC:

472556

AN:

1111956

Other (OTH)

AF:

0.371

AC:

22396

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

21027

42054

63082

84109

105136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14158

28316

42474

56632

70790

<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:

0.322

AC:

48927

AN:

152070

Hom.:

9089

Cov.:

AF XY:

0.319

AC XY:

23706

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.147

AC:

6087

AN:

41498

American (AMR)

AF:

0.392

AC:

5990

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.465

AC:

1616

AN:

3472

East Asian (EAS)

AF:

0.123

AC:

637

AN:

5162

South Asian (SAS)

AF:

0.159

AC:

767

AN:

4820

European-Finnish (FIN)

AF:

0.407

AC:

4307

AN:

10576

Middle Eastern (MID)

AF:

0.463

AC:

136

AN:

294

European-Non Finnish (NFE)

AF:

0.414

AC:

28149

AN:

67934

Other (OTH)

AF:

0.380

AC:

802

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1662

3324

4985

6647

8309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

476

952

1428

1904

2380

<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:

0.381

Hom.:

23154

Bravo

AF:

0.317

Asia WGS

AF:

0.148

AC:

517

AN:

3478

EpiCase

AF:

0.426

EpiControl

AF:

0.430

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 18, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 18

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 08, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.57

PhyloP100

1.9

Mutation Taster

=68/32

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000031

dbscSNV1_RF

Benign

0.0060

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