rs147797700

chr1-43431825-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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 9.35

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=0.0057106614).
• 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 GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SZT2	NM_001365999.1	c.5198G>A	p.Arg1733His	missense_variant	36/72	ENST00000634258.3
SZT2	NM_015284.4	c.5027G>A	p.Arg1676His	missense_variant	35/71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SZT2	ENST00000634258.3	c.5198G>A	p.Arg1733His	missense_variant	36/72	5	NM_001365999.1	P1
SZT2	ENST00000562955.2	c.5027G>A	p.Arg1676His	missense_variant	35/71	5
SZT2	ENST00000648058.1	n.338G>A		non_coding_transcript_exon_variant	4/40

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1561 AN: 152176 Hom.: 13 Cov.: 32

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.: 22 AF XY: 0.0109 AC XY: 1483 AN XY: 135882

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.: 32 AF XY: 0.0139 AC XY: 10109 AN XY: 727242

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.: 13 Cov.: 32 AF XY: 0.0102 AC XY: 759 AN XY: 74456

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.: 20

Bravo AF: 0.0103

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.0131 AC: 113

ExAC AF: 0.0111 AC: 1349

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0128

EpiControl AF: 0.0145

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	Dec 30, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2019	- -

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	T
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.59	T
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	.;D
Vest4		0.26
MPC		1.0
ClinPred		0.017	T
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

Other links and lift over

dbSNP: rs147797700; hg19: chr1-43897496;