chr1-43431825-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365999.1(SZT2):c.5198G>A(p.Arg1733His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,614,174 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1733C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.010 ( 13 hom., cov: 32)

Exomes 𝑓: 0.014 ( 183 hom. )

Consequence

SZT2
NM_001365999.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.35

Publications

12 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 (MetaRNN=0.0057106614).

BP6

Variant 1-43431825-G-A is Benign according to our data. Variant chr1-43431825-G-A is described in ClinVar as Benign. ClinVar VariationId is 260616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0103 (1567/152296) while in subpopulation NFE AF = 0.0146 (995/68022). AF 95% confidence interval is 0.0139. There are 13 homozygotes in GnomAd4. There are 759 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SZT2	NM_001365999.1 link	c.5198G>A	p.Arg1733His	missense_variant	Exon 36 of 72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4 link	c.5027G>A	p.Arg1676His	missense_variant	Exon 35 of 71		NP_056099.3	Q5T011-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SZT2	ENST00000634258.3 link	c.5198G>A	p.Arg1733His	missense_variant	Exon 36 of 72	5	NM_001365999.1	ENSP00000489255.1	Q5T011-1
SZT2	ENST00000562955.2 link	c.5027G>A	p.Arg1676His	missense_variant	Exon 35 of 71	5		ENSP00000457168.1	Q5T011-5
SZT2	ENST00000648058.1 link	n.338G>A		non_coding_transcript_exon_variant	Exon 4 of 40
SZT2	ENST00000638642.1 link	n.*56G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0103

AC:

1561

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00569

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0127

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0106

Gnomad FIN

AF:

0.00330

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0146

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.0104

AC:

2619

AN:

251430

AF XY:

0.0109

show subpopulations

Gnomad AFR exome

AF:

0.00578

Gnomad AMR exome

AF:

0.00665

Gnomad ASJ exome

AF:

0.00476

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00411

Gnomad NFE exome

AF:

0.0154

Gnomad OTH exome

AF:

0.00961

GnomAD4 exome

AF:

0.0142

AC:

20705

AN:

1461878

Hom.:

183

Cov.:

AF XY:

0.0139

AC XY:

10109

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00523

AC:

175

AN:

33480

American (AMR)

AF:

0.00767

AC:

343

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00471

AC:

123

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0115

AC:

993

AN:

86256

European-Finnish (FIN)

AF:

0.00612

AC:

327

AN:

53412

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0161

AC:

17904

AN:

1112006

Other (OTH)

AF:

0.0129

AC:

777

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

1216

2433

3649

4866

6082

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

688

1376

2064

2752

3440

<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:

0.0103

AC:

1567

AN:

152296

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

759

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00580

AC:

241

AN:

41566

American (AMR)

AF:

0.0127

AC:

194

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.0108

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00330

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0146

AC:

995

AN:

68022

Other (OTH)

AF:

0.0128

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

160

239

319

399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0130

Hom.:

Bravo

AF:

0.0103

TwinsUK

AF:

0.0197

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.0131

AC:

113

ExAC

AF:

0.0111

AC:

1349

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0128

EpiControl

AF:

0.0145

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 02, 2019

GeneDx

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

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 2024

Athena Diagnostics

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

- -

Inborn genetic diseases

Benign:1

Apr 23, 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

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.8

L;.

PhyloP100

9.3

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.8

.;D

Sift

Uncertain

0.0030

.;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

.;D

Vest4

0.26

MPC

1.0

ClinPred

0.017

GERP RS

5.8

Varity_R

0.37

gMVP

0.50

Mutation Taster

=96/4

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