rs181831231

Positions:

• chr1-43442432-C-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.7975-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,612,080 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (34 hom.)
• Consequence: SZT2 NM_001365999.1 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001176
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.858

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=-0.92).
• BP6: Variant 1-43442432-C-T is Benign according to our data. Variant chr1-43442432-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 416958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43442432-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00145 (221/152292) while in subpopulation EAS AF= 0.0253 (131/5184). AF 95% confidence interval is 0.0218. There are 0 homozygotes in gnomad4. There are 115 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SZT2	NM_001365999.1	c.7975-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4	c.7804-10C>T		splice_polypyrimidine_tract_variant, intron_variant			NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3	c.7975-10C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001365999.1	ENSP00000489255	P1
SZT2	ENST00000562955.2	c.7804-10C>T		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000457168
SZT2	ENST00000648058.1	n.4429-10C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant
SZT2	ENST00000649403.1	n.2725-10C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 222 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0254

Gnomad SAS AF: 0.00891

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00399 AC: 996 AN: 249586 Hom.: 8 AF XY: 0.00402 AC XY: 542 AN XY: 134796

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00605

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0280

Gnomad SAS exome AF: 0.00809

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00145 AC: 2112 AN: 1459788 Hom.: 34 Cov.: 36 AF XY: 0.00168 AC XY: 1223 AN XY: 725914

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00531

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0205

Gnomad4 SAS exome AF: 0.00827

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000693

Gnomad4 OTH exome AF: 0.00446

GnomAD4 genome AF: 0.00145 AC: 221 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74468

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0253

Gnomad4 SAS AF: 0.00892

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000646 Hom.: 0

Bravo AF: 0.00183

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Developmental and epileptic encephalopathy, 18 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

SZT2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2019

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	-0.92
CADD	Benign	6.1
DANN	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.038
SpliceAI score (max)		0.020		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: rs181831231; hg19: chr1-43908103;