rs578153834

chr1-43423096-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365999.1(SZT2):c.2038-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000959 in 1,584,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: SZT2 NM_001365999.1 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001899
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.25

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SZT2	NM_001365999.1	c.2038-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000634258.3
SZT2	NM_015284.4	c.2038-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SZT2	ENST00000634258.3	c.2038-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001365999.1	P1
SZT2	ENST00000562955.2	c.2038-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5
SZT2	ENST00000470139.1	c.769-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000105 AC: 22 AN: 209474 Hom.: 0 AF XY: 0.0000692 AC XY: 8 AN XY: 115552

Gnomad AFR exome AF: 0.00146

Gnomad AMR exome AF: 0.000126

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000184

GnomAD4 exome AF: 0.0000496 AC: 71 AN: 1431932 Hom.: 0 Cov.: 32 AF XY: 0.0000281 AC XY: 20 AN XY: 711426

Gnomad4 AFR exome AF: 0.00181

Gnomad4 AMR exome AF: 0.000118

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.0000836

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74452

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000712 Hom.: 0

Bravo AF: 0.000582

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 18 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2017

The c.2038-3C>T intronic variant results from a C to T substitution 3 nucleotides upstream from N/A in the SZT2 gene. This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 27, 2022

This sequence change falls in intron 14 of the SZT2 gene. It does not directly change the encoded amino acid sequence of the SZT2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs578153834, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with SZT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 411938). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	13
Dann	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0019
dbscSNV1_RF	Benign	0.058
SpliceAI score (max)		0.11		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: rs578153834; hg19: chr1-43888767;