rs150113647

Positions:

chr1-43441554-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365999.1(SZT2):c.7562T>C(p.Val2521Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00435 in 1,614,118 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2521M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 21 hom. )

Consequence

SZT2
NM_001365999.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.09

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:

SZT2 (HGNC:):

SZT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SZT2. . Gene score misZ 2.5968 (greater than the threshold 3.09). Trascript score misZ 4.0086 (greater than threshold 3.09). GenCC has associacion of gene with undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy, 18, developmental and epileptic encephalopathy.

BP4

Computational evidence support a benign effect (MetaRNN=0.009698093).

BP6

Variant 1-43441554-T-C is Benign according to our data. Variant chr1-43441554-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 235494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43441554-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0033 (503/152232) while in subpopulation NFE AF= 0.00591 (402/67994). AF 95% confidence interval is 0.00544. There are 0 homozygotes in gnomad4. There are 228 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SZT2	NM_001365999.1 linkuse as main transcript	c.7562T>C	p.Val2521Ala	missense_variant	54/72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4 linkuse as main transcript	c.7391T>C	p.Val2464Ala	missense_variant	53/71		NP_056099.3	Q5T011-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SZT2	ENST00000634258.3 linkuse as main transcript	c.7562T>C	p.Val2521Ala	missense_variant	54/72	5	NM_001365999.1	ENSP00000489255.1	Q5T011-1
SZT2	ENST00000562955.2 linkuse as main transcript	c.7391T>C	p.Val2464Ala	missense_variant	53/71	5		ENSP00000457168.1	Q5T011-5
SZT2	ENST00000648058.1 linkuse as main transcript	n.4016T>C		non_coding_transcript_exon_variant	22/40
SZT2	ENST00000649403.1 linkuse as main transcript	n.2312T>C		non_coding_transcript_exon_variant	19/37

Frequencies

GnomAD3 genomes

AF:

0.00331

AC:

504

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00591

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.00417

AC:

1048

AN:

251402

Hom.:

AF XY:

0.00448

AC XY:

609

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00263

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00762

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00446

AC:

6524

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

3179

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00284

Gnomad4 ASJ exome

AF:

0.00180

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00125

Gnomad4 FIN exome

AF:

0.00109

Gnomad4 NFE exome

AF:

0.00529

Gnomad4 OTH exome

AF:

0.00404

GnomAD4 genome

AF:

0.00330

AC:

503

AN:

152232

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

228

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000963

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.000566

Gnomad4 NFE

AF:

0.00591

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00518

Hom.:

Bravo

AF:

0.00352

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00526

AC:

638

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00709

EpiControl

AF:

0.00806

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	SZT2: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Developmental and epileptic encephalopathy, 18

Benign:1

Likely 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

Oct 04, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2018

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. -

SZT2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

0.10

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.52

T;T

M_CAP

Benign

0.0047

MetaRNN

Benign

0.0097

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.8

.;N

Sift

Benign

0.033

.;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.40

.;B

Vest4

0.71

MVP

0.50

MPC

0.53

ClinPred

0.0061

GERP RS

4.4

Varity_R

0.037

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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