chr1-43430742-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001365999.1(SZT2):c.4727G>A(p.Arg1576His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,612,696 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1576C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

SZT2
NM_001365999.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 2.84

Publications

1 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=0.011859179).

BP6

Variant 1-43430742-G-A is Benign according to our data. Variant chr1-43430742-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436931.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00111 (169/152334) while in subpopulation AFR AF = 0.00395 (164/41568). AF 95% confidence interval is 0.00345. There are 0 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SZT2	NM_001365999.1 link	c.4727G>A	p.Arg1576His	missense_variant	Exon 32 of 72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4 link	c.4556G>A	p.Arg1519His	missense_variant	Exon 31 of 71		NP_056099.3	Q5T011-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SZT2	ENST00000634258.3 link	c.4727G>A	p.Arg1576His	missense_variant	Exon 32 of 72	5	NM_001365999.1	ENSP00000489255.1	Q5T011-1
SZT2	ENST00000562955.2 link	c.4556G>A	p.Arg1519His	missense_variant	Exon 31 of 71	5		ENSP00000457168.1	Q5T011-5
SZT2	ENST00000478140.1 link	n.*45G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

166

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000253

AC:

AN:

249424

AF XY:

0.000163

show subpopulations

Gnomad AFR exome

AF:

0.00346

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000130

AC:

190

AN:

1460362

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

726520

show subpopulations

African (AFR)

AF:

0.00418

AC:

140

AN:

33480

American (AMR)

AF:

0.000201

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51976

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111964

Other (OTH)

AF:

0.000447

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.00111

AC:

169

AN:

152334

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00395

AC:

164

AN:

41568

American (AMR)

AF:

0.000196

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000450

Hom.:

Bravo

AF:

0.00119

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000288

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 19, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Dec 27, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 18

Uncertain:1

Dec 20, 2021

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Feb 23, 2019

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R1519H variant (also known as c.4556G>A), located in coding exon 31 of the SZT2 gene, results from a G to A substitution at nucleotide position 4556. The arginine at codon 1519 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and histidine is the reference amino acid in other 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-0.16

Eigen_PC

Benign

0.017

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-1.1

PhyloP100

2.8

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.7

.;N

Sift

Benign

0.14

.;T

Sift4G

Benign

0.20

T;T

Polyphen

0.0040

.;B

Vest4

0.17

MVP

0.38

MPC

0.33

ClinPred

0.021

GERP RS

3.9

Varity_R

0.037

gMVP

0.36

Mutation Taster

=80/20

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