1-43432591-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001365999.1(SZT2):c.5517C>T(p.Arg1839Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,613,654 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1839R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0071 ( 12 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 11 hom. )

Consequence

SZT2
NM_001365999.1 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.383

Publications

2 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant 1-43432591-C-T is Benign according to our data. Variant chr1-43432591-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.383 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00708 (1078/152274) while in subpopulation AFR AF = 0.0243 (1009/41556). AF 95% confidence interval is 0.023. There are 12 homozygotes in GnomAd4. There are 487 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SZT2	NM_001365999.1 link	c.5517C>T	p.Arg1839Arg	synonymous_variant	Exon 38 of 72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4 link	c.5346C>T	p.Arg1782Arg	synonymous_variant	Exon 37 of 71		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3 link	c.5517C>T	p.Arg1839Arg	synonymous_variant	Exon 38 of 72	5	NM_001365999.1	ENSP00000489255.1

Frequencies

GnomAD3 genomes

AF:

0.00705

AC:

1073

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00623

GnomAD2 exomes

AF:

0.00189

AC:

473

AN:

250438

AF XY:

0.00135

show subpopulations

Gnomad AFR exome

AF:

0.0261

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000738

AC:

1078

AN:

1461380

Hom.:

Cov.:

AF XY:

0.000651

AC XY:

473

AN XY:

727032

show subpopulations

African (AFR)

AF:

0.0244

AC:

817

AN:

33478

American (AMR)

AF:

0.00136

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26066

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000926

AC:

103

AN:

1111740

Other (OTH)

AF:

0.00139

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

120

181

241

301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00708

AC:

1078

AN:

152274

Hom.:

Cov.:

AF XY:

0.00654

AC XY:

487

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0243

AC:

1009

AN:

41556

American (AMR)

AF:

0.00301

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68026

Other (OTH)

AF:

0.00617

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

148

198

247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.00815

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Oct 11, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 05, 2018

Athena Diagnostics

Significance: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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Mar 18, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.63

PhyloP100

0.38

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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