rs2255632

chr1-43443594-T-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.8626-3T>C 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 0.385 in 1,613,750 control chromosomes in the GnomAD database, including 126,714 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9089 hom., cov: 32)
  • Exomes 𝑓: 0.39 (117625 hom.)
• Consequence: SZT2 NM_001365999.1 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003135
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.92

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=-0.74).
• BP6: Variant 1-43443594-T-C is Benign according to our data. Variant chr1-43443594-T-C is described in ClinVar as [Benign]. Clinvar id is 260626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SZT2	NM_001365999.1	c.8626-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000634258.3
SZT2	NM_015284.4	c.8455-3T>C		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.8626-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001365999.1	P1

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48915 AN: 151952 Hom.: 9090 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.414

Gnomad OTH AF: 0.382

GnomAD3 exomes AF: 0.337 AC: 84632 AN: 251052 Hom.: 16258 AF XY: 0.337 AC XY: 45706 AN XY: 135726

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.330

Gnomad ASJ exome AF: 0.471

Gnomad EAS exome AF: 0.112

Gnomad SAS exome AF: 0.165

Gnomad FIN exome AF: 0.411

Gnomad NFE exome AF: 0.422

Gnomad OTH exome AF: 0.381

GnomAD4 exome AF: 0.391 AC: 571782 AN: 1461680 Hom.: 117625 Cov.: 61 AF XY: 0.386 AC XY: 280696 AN XY: 727152

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.340

Gnomad4 ASJ exome AF: 0.468

Gnomad4 EAS exome AF: 0.158

Gnomad4 SAS exome AF: 0.169

Gnomad4 FIN exome AF: 0.404

Gnomad4 NFE exome AF: 0.425

Gnomad4 OTH exome AF: 0.371

GnomAD4 genome AF: 0.322 AC: 48927 AN: 152070 Hom.: 9089 Cov.: 32 AF XY: 0.319 AC XY: 23706 AN XY: 74336

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.392

Gnomad4 ASJ AF: 0.465

Gnomad4 EAS AF: 0.123

Gnomad4 SAS AF: 0.159

Gnomad4 FIN AF: 0.407

Gnomad4 NFE AF: 0.414

Gnomad4 OTH AF: 0.380

Alfa AF: 0.383 Hom.: 8893

Bravo AF: 0.317

Asia WGS AF: 0.148 AC: 517 AN: 3478

EpiCase AF: 0.426

EpiControl AF: 0.430

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2018	- -

Developmental and epileptic encephalopathy, 18 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 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
BayesDel_noAF	Benign	-0.74
Cadd	Benign	13
Dann	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.0060
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: rs2255632; hg19: chr1-43909265; COSMIC: COSV65167141; COSMIC: COSV65167141;