rs117106532

Variant names:

• chr1-43441501-C-T
• rs117106532
• NM_001365999.1:c.7512-3C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365999.1(SZT2):​c.7512-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,613,066 control chromosomes in the GnomAD database, including 33 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (33 hom.)
• Consequence: SZT2 NM_001365999.1 splice_region, intron
• Scores: Splicing: ADA: 0.0002041
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0510

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=-0.73).
• BP6: Variant 1-43441501-C-T is Benign according to our data. Variant chr1-43441501-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 416968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43441501-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00133 (203/152310) while in subpopulation EAS AF= 0.0255 (132/5186). AF 95% confidence interval is 0.0219. There are 0 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SZT2	NM_001365999.1	c.7512-3C>T		splice_region_variant, intron_variant	Intron 53 of 71	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4	c.7341-3C>T		splice_region_variant, intron_variant	Intron 52 of 70		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3	c.7512-3C>T		splice_region_variant, intron_variant	Intron 53 of 71	5	NM_001365999.1	ENSP00000489255.1
SZT2	ENST00000562955.2	c.7341-3C>T		splice_region_variant, intron_variant	Intron 52 of 70	5		ENSP00000457168.1
SZT2	ENST00000648058.1	n.3966-3C>T		splice_region_variant, intron_variant	Intron 21 of 39
SZT2	ENST00000649403.1	n.2262-3C>T		splice_region_variant, intron_variant	Intron 18 of 36

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00318 AC: 796 AN: 250140 Hom.: 7 AF XY: 0.00346 AC XY: 468 AN XY: 135084

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0279

Gnomad SAS exome AF: 0.00813

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00128 AC: 1872 AN: 1460756 Hom.: 33 Cov.: 49 AF XY: 0.00155 AC XY: 1125 AN XY: 726612

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0205

Gnomad4 SAS exome AF: 0.00826

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.00441

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.00144 AC XY: 107 AN XY: 74486

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0255

Gnomad4 SAS AF: 0.00911

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.00136

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 20, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 18 Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jun 12, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

SZT2-related disorder Benign:1

Aug 09, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.81
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.026
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: rs117106532; hg19: chr1-43907172; COSMIC: COSV65170310; COSMIC: COSV65170310;