rs72671125

chr1-43439615-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.6888C>T(p.Cys2296=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0233 in 1,613,892 control chromosomes in the GnomAD database, including 507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (39 hom., cov: 33)
  • Exomes 𝑓: 0.024 (468 hom.)
• Consequence: SZT2 NM_001365999.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.48

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=-0.48).
• BP6: Variant 1-43439615-C-T is Benign according to our data. Variant chr1-43439615-C-T is described in ClinVar as [Benign]. Clinvar id is 241036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43439615-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0193 (2939/152330) while in subpopulation NFE AF= 0.0277 (1884/68012). AF 95% confidence interval is 0.0267. There are 39 homozygotes in gnomad4. There are 1461 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SZT2	NM_001365999.1	c.6888C>T	p.Cys2296=	synonymous_variant	50/72	ENST00000634258.3
SZT2	NM_015284.4	c.6717C>T	p.Cys2239=	synonymous_variant	49/71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SZT2	ENST00000634258.3	c.6888C>T	p.Cys2296=	synonymous_variant	50/72	5	NM_001365999.1	P1

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2940 AN: 152212 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.00458

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00558

Gnomad FIN AF: 0.0417

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0277

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0203 AC: 5086 AN: 250364 Hom.: 82 AF XY: 0.0206 AC XY: 2793 AN XY: 135532

Gnomad AFR exome AF: 0.00370

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0132

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00588

Gnomad FIN exome AF: 0.0439

Gnomad NFE exome AF: 0.0288

Gnomad OTH exome AF: 0.0239

GnomAD4 exome AF: 0.0237 AC: 34598 AN: 1461562 Hom.: 468 Cov.: 33 AF XY: 0.0234 AC XY: 16994 AN XY: 727078

Gnomad4 AFR exome AF: 0.00311

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.0130

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00651

Gnomad4 FIN exome AF: 0.0428

Gnomad4 NFE exome AF: 0.0266

Gnomad4 OTH exome AF: 0.0199

GnomAD4 genome AF: 0.0193 AC: 2939 AN: 152330 Hom.: 39 Cov.: 33 AF XY: 0.0196 AC XY: 1461 AN XY: 74490

Gnomad4 AFR AF: 0.00457

Gnomad4 AMR AF: 0.0204

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.0417

Gnomad4 NFE AF: 0.0277

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0232 Hom.: 20

Bravo AF: 0.0171

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0257

EpiControl AF: 0.0260

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	Aug 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Developmental and epileptic encephalopathy, 18 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 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	-0.48
Cadd	Benign	15
Dann	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs72671125; hg19: chr1-43905286;