Variant rs746200792 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong

The NM_001365999.1(SZT2):c.6120_6122del(p.Val2041del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

SZT2
NM_001365999.1 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 8.02

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_001365999.1. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 1-43437253-CGTT-C is Pathogenic according to our data. Variant chr1-43437253-CGTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SZT2	NM_001365999.1 linkuse as main transcript	c.6120_6122del	p.Val2041del	inframe_deletion	43/72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4 linkuse as main transcript	c.5949_5951del	p.Val1984del	inframe_deletion	42/71		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3 linkuse as main transcript	c.6120_6122del	p.Val2041del	inframe_deletion	43/72	5	NM_001365999.1	ENSP00000489255	P1	Q5T011-1

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251458

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1461894

Hom.:

AF XY:

0.0000550

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 18

Pathogenic:3Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	May 31, 2023	PS3_Supporting, PM2, PM3_Strong, PM4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This 3-base-pair in-frame deletion variant found in exon 42 of 71 leads to the loss of 1 amino acid residue but preserves the reading frame. This variant has been previously reported together with a second variant in SZT2 in individuals with global developmental delay, seizures, and hypotonia (PMID: 30755392, 30564332). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (18/282850) and is absent in the homozygous state. Based on the available evidence, c.5949_5951del (p.Val1984del) is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Oct 06, 2022	The heterozygous p.Val2041del variant was identified by our study in one individual with early infantile encephalopathy. Trio exome analysis revealed that this variant was in trans with a variant of uncertain significance. The p.Val1984del variant has been reported in five affected individuals (PMID: 30564332, 30755392, 35773235) but has been identified in 9/10370 (0.087%) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs756197807). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 372895) and has been interpreted as likely pathogenic by GeneDx, Children’s Hospital of Philadelphia Division of Genomic Diagnostics, and Children’s Hospital Los Angeles Center for Personalized Medicine and as a variant of uncertain significance by Invitae. Of the five affected individuals previously reported, two were homozygotes (PMID: 35773235) and two were compound heterozygotes who carried a likely pathogenic variant in trans (PMID: 30755392, PMID: 35773235), which increases the likelihood that the p.Val2041del variant is pathogenic. In vitro functional studies provide some evidence that the p.Val2041del variant may slightly impact protein function (PMID: 35773235). However, these types of assays may not accurately represent biological function. This variant is a deletion of one amino acid at position 1984 and is not predicted to alter the protein reading-frame. This deletion may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive developmental and epileptic encephalopathy 18. ACMG/AMP Criteria applied: PM3_Strong, PS3_Supporting, PM2_Supporting, PM4_Supporting (Richards 2015). -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Likely pathogenic and reported on 06-02-2016 by Lab or GTR ID 506013. Variant also interpretted as Likley pathogenic and reported on 08-22-2019 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2016	The c.5949_5951delTGT variant in the SZT2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.5949_5951delTGT variant results in an in-frame 3 base pair deletion and is predicted to cause loss of a Valine residue at position 1984 in the protein, denoted as p.Val1984del. The c.5949_5951delTGT variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Thus, the c.5949_5951delTGT variant is a strong candidate for pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	SZT2: PM3:Strong, PM2, PM4:Supporting, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2023	This variant, c.5949_5951del, results in the deletion of 1 amino acid(s) of the SZT2 protein (p.Val1984del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs746200792, gnomAD 0.09%). This variant has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (PMID: 30564332, 30755392, 35773235; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 372895). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SZT2 function (PMID: 30564332, 35773235). For these reasons, this variant has been classified as Pathogenic. -

Cryptorchidism;C0036572:Seizure;C0557874:Global developmental delay;C0948163:Abnormal cerebral white matter morphology;C1842364:Central hypotonia;C1857953:Deep plantar creases;C2243051:Macrocephaly;C4025875:Abnormal anterior fontanelle morphology

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

- -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

Dec 21, 2022

- -

SZT2-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2024

The SZT2 c.5949_5951delTGT variant is predicted to result in an in-frame deletion (p.Val1984del). This variant has been reported in the compound heterozygous state and homozygous state in at least four individuals with epileptic encephalopathy (Uittenbogaard et al. 2018. PubMed ID: 30564332; Calhoun et al. 2022. PubMed ID: 35773235). In vitro studies suggest that this variant alters protein function (Uittenbogaard et al. 2018. PubMed ID: 30564332). This variant is reported in 0.087% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Taken together, this variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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