1-43438733-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001365999.1(SZT2):c.6543A>G(p.Leu2181Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00627 in 1,614,064 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2181L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0050 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0064 ( 49 hom. )

Consequence

SZT2
NM_001365999.1 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.11

Variant links:

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]

SZT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 1-43438733-A-G is Benign according to our data. Variant chr1-43438733-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 260621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43438733-A-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=2.11 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00503 (765/152216) while in subpopulation NFE AF= 0.00704 (479/68006). AF 95% confidence interval is 0.00652. There are 5 homozygotes in gnomad4. There are 373 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SZT2	NM_001365999.1 link	c.6543A>G	p.Leu2181Leu	synonymous_variant	Exon 47 of 72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4 link	c.6372A>G	p.Leu2124Leu	synonymous_variant	Exon 46 of 71		NP_056099.3	Q5T011-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3 link	c.6543A>G	p.Leu2181Leu	synonymous_variant	Exon 47 of 72	5	NM_001365999.1	ENSP00000489255.1		Q5T011-1

Frequencies

GnomAD3 genomes

AF:

0.00502

AC:

764

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00704

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00528

AC:

1328

AN:

251348

Hom.:

AF XY:

0.00534

AC XY:

726

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.00198

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.0148

Gnomad NFE exome

AF:

0.00724

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00640

AC:

9355

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00622

AC XY:

4522

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.00237

Gnomad4 ASJ exome

AF:

0.00176

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00145

Gnomad4 FIN exome

AF:

0.0143

Gnomad4 NFE exome

AF:

0.00719

Gnomad4 OTH exome

AF:

0.00440

GnomAD4 genome

AF:

0.00503

AC:

765

AN:

152216

Hom.:

Cov.:

AF XY:

0.00501

AC XY:

373

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00154

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0151

Gnomad4 NFE

AF:

0.00704

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00524

Hom.:

Bravo

AF:

0.00437

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00616

EpiControl

AF:

0.00634

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SZT2: BP4, BP7, BS2 -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Developmental and epileptic encephalopathy, 18

Benign:2

Oct 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 16, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 15, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-0.65

CADD

Benign

6.5

DANN

Benign

0.39

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over