rs2039531

Positions:

• chr1-43435340-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365999.1(SZT2):​c.6034+11A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 1,612,742 control chromosomes in the GnomAD database, including 121,820 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8608 hom., cov: 33)
  • Exomes 𝑓: 0.38 (113212 hom.)
• Consequence: SZT2 NM_001365999.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.166

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 1-43435340-A-C is Benign according to our data. Variant chr1-43435340-A-C is described in ClinVar as [Benign]. Clinvar id is 260619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SZT2	NM_001365999.1	c.6034+11A>C		intron_variant		ENST00000634258.3
SZT2	NM_015284.4	c.5863+11A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SZT2	ENST00000634258.3	c.6034+11A>C		intron_variant		5	NM_001365999.1	P1
SZT2	ENST00000562955.2	c.5863+11A>C		intron_variant		5
SZT2	ENST00000648058.1	n.2488+11A>C		intron_variant, non_coding_transcript_variant
SZT2	ENST00000649403.1	n.784+11A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47397 AN: 151930 Hom.: 8610 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.0743

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.371

GnomAD3 exomes AF: 0.325 AC: 81260 AN: 249812 Hom.: 15248 AF XY: 0.325 AC XY: 43846 AN XY: 135008

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.436

Gnomad EAS exome AF: 0.0669

Gnomad SAS exome AF: 0.154

Gnomad FIN exome AF: 0.400

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.383 AC: 558898 AN: 1460694 Hom.: 113212 Cov.: 36 AF XY: 0.377 AC XY: 273944 AN XY: 726630

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.334

Gnomad4 ASJ exome AF: 0.433

Gnomad4 EAS exome AF: 0.100

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.392

Gnomad4 NFE exome AF: 0.419

Gnomad4 OTH exome AF: 0.360

GnomAD4 genome AF: 0.312 AC: 47415 AN: 152048 Hom.: 8608 Cov.: 33 AF XY: 0.308 AC XY: 22878 AN XY: 74290

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.381

Gnomad4 ASJ AF: 0.426

Gnomad4 EAS AF: 0.0743

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.391

Gnomad4 NFE AF: 0.408

Gnomad4 OTH AF: 0.369

Alfa AF: 0.302 Hom.: 1368

Bravo AF: 0.307

Asia WGS AF: 0.129 AC: 448 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Developmental and epileptic encephalopathy, 18 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.1
DANN	Benign	0.63

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: rs2039531; hg19: chr1-43901011; COSMIC: COSV65170599; COSMIC: COSV65170599;