rs76675748

chr1-43430546-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365999.1(SZT2):c.4531G>A(p.Val1511Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,614,228 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts 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. V1511A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (38 hom.)
• Consequence: SZT2 NM_001365999.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 9.42

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SZT2
• BP4: Computational evidence support a benign effect (MetaRNN=0.008562744).
• BP6: Variant 1-43430546-G-A is Benign according to our data. Variant chr1-43430546-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43430546-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00356 (542/152342) while in subpopulation NFE AF= 0.00607 (413/68030). AF 95% confidence interval is 0.00559. There are 1 homozygotes in gnomad4. There are 267 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SZT2	NM_001365999.1	c.4531G>A	p.Val1511Ile	missense_variant	32/72	ENST00000634258.3
SZT2	NM_015284.4	c.4360G>A	p.Val1454Ile	missense_variant	31/71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SZT2	ENST00000634258.3	c.4531G>A	p.Val1511Ile	missense_variant	32/72	5	NM_001365999.1	P1
SZT2	ENST00000562955.2	c.4360G>A	p.Val1454Ile	missense_variant	31/71	5
SZT2	ENST00000478140.1	n.392G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00356 AC: 542 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00607

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00353 AC: 888 AN: 251426 Hom.: 6 AF XY: 0.00353 AC XY: 480 AN XY: 135878

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00212

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00577

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00515 AC: 7525 AN: 1461886 Hom.: 38 Cov.: 33 AF XY: 0.00503 AC XY: 3661 AN XY: 727246

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.00286

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00225

Gnomad4 FIN exome AF: 0.000374

Gnomad4 NFE exome AF: 0.00616

Gnomad4 OTH exome AF: 0.00374

GnomAD4 genome AF: 0.00356 AC: 542 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00358 AC XY: 267 AN XY: 74494

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00607

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00539 Hom.: 1

Bravo AF: 0.00365

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00349 AC: 424

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00522

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SZT2: BS2 -

Developmental and epileptic encephalopathy, 18 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 19, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 30, 2019	This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 18, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 15, 2020	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2019

This variant is classified as likely 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	0.32
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.069	T;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	D;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.0086	T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	0.87	D;D
PrimateAI	Uncertain	0.58	T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.39
MVP		0.37
MPC		0.83
ClinPred		0.028	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.22

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

Other links and lift over

dbSNP: rs76675748; hg19: chr1-43896217;