chr1-43441554-T-C

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.7562T>C(p.Val2521Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00435 in 1,614,118 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2521M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 21 hom. )

Consequence

SZT2
NM_001365999.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.09

Publications

10 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=0.009698093).

BP6

Variant 1-43441554-T-C is Benign according to our data. Variant chr1-43441554-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235494.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 = 0.0033 (503/152232) while in subpopulation NFE AF = 0.00591 (402/67994). AF 95% confidence interval is 0.00544. There are 0 homozygotes in GnomAd4. There are 228 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 21 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SZT2	NM_001365999.1 link	c.7562T>C	p.Val2521Ala	missense_variant	Exon 54 of 72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4 link	c.7391T>C	p.Val2464Ala	missense_variant	Exon 53 of 71		NP_056099.3	Q5T011-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SZT2	ENST00000634258.3 link	c.7562T>C	p.Val2521Ala	missense_variant	Exon 54 of 72	5	NM_001365999.1	ENSP00000489255.1	Q5T011-1
SZT2	ENST00000562955.2 link	c.7391T>C	p.Val2464Ala	missense_variant	Exon 53 of 71	5		ENSP00000457168.1	Q5T011-5
SZT2	ENST00000648058.1 link	n.4016T>C		non_coding_transcript_exon_variant	Exon 22 of 40
SZT2	ENST00000649403.1 link	n.2312T>C		non_coding_transcript_exon_variant	Exon 19 of 37

Frequencies

GnomAD3 genomes

AF:

0.00331

AC:

504

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00591

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00417

AC:

1048

AN:

251402

AF XY:

0.00448

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00263

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00762

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00446

AC:

6524

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

3179

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33480

American (AMR)

AF:

0.00284

AC:

127

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00180

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00125

AC:

108

AN:

86256

European-Finnish (FIN)

AF:

0.00109

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00468

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00529

AC:

5887

AN:

1112010

Other (OTH)

AF:

0.00404

AC:

244

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

442

884

1327

1769

2211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

368

552

736

920

<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:

0.00330

AC:

503

AN:

152232

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

228

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000963

AC:

AN:

41544

American (AMR)

AF:

0.00261

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000830

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00591

AC:

402

AN:

67994

Other (OTH)

AF:

0.00237

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

113

141

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:

0.00540

Hom.:

Bravo

AF:

0.00352

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00526

AC:

638

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00709

EpiControl

AF:

0.00806

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SZT2: BP4, BS2 -

Feb 04, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 20, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Oct 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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jun 05, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

SZT2-related disorder

Benign:1

Jun 26, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

0.18

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

0.10

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.52

T;T

M_CAP

Benign

0.0047

MetaRNN

Benign

0.0097

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.

PhyloP100

4.1

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.8

.;N

Sift

Benign

0.033

.;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.40

.;B

Vest4

0.71

MVP

0.50

MPC

0.53

ClinPred

0.0061

GERP RS

4.4

Varity_R

0.037

gMVP

0.57

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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