rs147797700

Positions:

chr1-43431825-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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

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 links:

SZT2 (HGNC:):

SZT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SZT2. . Gene score misZ 2.5968 (greater than the threshold 3.09). Trascript score misZ 4.0086 (greater than threshold 3.09). GenCC has associacion of gene with undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy, 18, developmental and epileptic encephalopathy.

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 id is 260616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43431825-G-A is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SZT2	NM_001365999.1 linkuse as main transcript	c.5198G>A	p.Arg1733His	missense_variant	36/72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4 linkuse as main transcript	c.5027G>A	p.Arg1676His	missense_variant	35/71		NP_056099.3	Q5T011-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SZT2	ENST00000634258.3 linkuse as main transcript	c.5198G>A	p.Arg1733His	missense_variant	36/72	5	NM_001365999.1	ENSP00000489255.1	Q5T011-1
SZT2	ENST00000562955.2 linkuse as main transcript	c.5027G>A	p.Arg1676His	missense_variant	35/71	5		ENSP00000457168.1	Q5T011-5
SZT2	ENST00000648058.1 linkuse as main transcript	n.338G>A		non_coding_transcript_exon_variant	4/40

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

GnomAD3 exomes

AF:

0.0104

AC:

2619

AN:

251430

Hom.:

AF XY:

0.0109

AC XY:

1483

AN XY:

135882

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 SAS exome

AF:

0.0114

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

Gnomad4 AFR exome

AF:

0.00523

Gnomad4 AMR exome

AF:

0.00767

Gnomad4 ASJ exome

AF:

0.00471

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0115

Gnomad4 FIN exome

AF:

0.00612

Gnomad4 NFE exome

AF:

0.0161

Gnomad4 OTH exome

AF:

0.0129

GnomAD4 genome

AF:

0.0103

AC:

1567

AN:

152296

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

759

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00580

Gnomad4 AMR

AF:

0.0127

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0108

Gnomad4 FIN

AF:

0.00330

Gnomad4 NFE

AF:

0.0146

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0137

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 04, 2024	- -

Developmental and epileptic encephalopathy, 18

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2016

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

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;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over