rs111932993

Positions:

• chr1-43430716-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001365999.1(SZT2):​c.4701G>A​(p.Leu1567=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000959 in 1,613,602 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (4 hom.)
• Consequence: SZT2 NM_001365999.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.33

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 1-43430716-G-A is Benign according to our data. Variant chr1-43430716-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 586765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00546 (832/152320) while in subpopulation AFR AF= 0.0192 (798/41574). AF 95% confidence interval is 0.0181. There are 8 homozygotes in gnomad4. There are 392 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SZT2	NM_001365999.1	c.4701G>A	p.Leu1567=	synonymous_variant	32/72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4	c.4530G>A	p.Leu1510=	synonymous_variant	31/71		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3	c.4701G>A	p.Leu1567=	synonymous_variant	32/72	5	NM_001365999.1	ENSP00000489255	P1
SZT2	ENST00000562955.2	c.4530G>A	p.Leu1510=	synonymous_variant	31/71	5		ENSP00000457168
SZT2	ENST00000478140.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00547 AC: 833 AN: 152202 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00146 AC: 367 AN: 250668 Hom.: 5 AF XY: 0.00118 AC XY: 160 AN XY: 135520

Gnomad AFR exome AF: 0.0203

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000489 AC: 715 AN: 1461282 Hom.: 4 Cov.: 32 AF XY: 0.000407 AC XY: 296 AN XY: 726936

Gnomad4 AFR exome AF: 0.0175

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00546 AC: 832 AN: 152320 Hom.: 8 Cov.: 32 AF XY: 0.00526 AC XY: 392 AN XY: 74476

Gnomad4 AFR AF: 0.0192

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00282 Hom.: 1

Bravo AF: 0.00606

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 18, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Developmental and epileptic encephalopathy, 18 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2016

This alteration is classified as likely 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	-0.47
CADD	Benign	4.6
DANN	Benign	0.70

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: rs111932993; hg19: chr1-43896387;