rs41312024

Positions:

• chr1-43404400-C-A
• chr1-43404400-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001365999.1(SZT2):​c.348C>A​(p.Ile116=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,613,574 control chromosomes in the GnomAD database, including 204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (21 hom., cov: 32)
  • Exomes 𝑓: 0.014 (183 hom.)
• Consequence: SZT2 NM_001365999.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.05

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 1-43404400-C-A is Benign according to our data. Variant chr1-43404400-C-A is described in ClinVar as [Benign]. Clinvar id is 416961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0119 (1817/152276) while in subpopulation NFE AF= 0.0181 (1229/68026). AF 95% confidence interval is 0.0172. There are 21 homozygotes in gnomad4. There are 888 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SZT2	NM_001365999.1	c.348C>A	p.Ile116=	synonymous_variant	4/72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4	c.348C>A	p.Ile116=	synonymous_variant	4/71		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3	c.348C>A	p.Ile116=	synonymous_variant	4/72	5	NM_001365999.1	ENSP00000489255	P1

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1818 AN: 152158 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0131

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0114 AC: 2868 AN: 250858 Hom.: 23 AF XY: 0.0113 AC XY: 1535 AN XY: 135552

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.00797

Gnomad ASJ exome AF: 0.00757

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0182

Gnomad OTH exome AF: 0.0133

GnomAD4 exome AF: 0.0144 AC: 21003 AN: 1461298 Hom.: 183 Cov.: 30 AF XY: 0.0141 AC XY: 10229 AN XY: 726884

Gnomad4 AFR exome AF: 0.00251

Gnomad4 AMR exome AF: 0.00850

Gnomad4 ASJ exome AF: 0.00877

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00121

Gnomad4 FIN exome AF: 0.0131

Gnomad4 NFE exome AF: 0.0169

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.0119 AC: 1817 AN: 152276 Hom.: 21 Cov.: 32 AF XY: 0.0119 AC XY: 888 AN XY: 74448

Gnomad4 AFR AF: 0.00390

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0131

Gnomad4 NFE AF: 0.0181

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0112 Hom.: 4

Bravo AF: 0.0120

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0158

EpiControl AF: 0.0144

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2019	- -

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

Athena Diagnostics

Jun 30, 2017

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 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	-0.28
CADD	Benign	12
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs41312024; hg19: chr1-43870071;