chr1-43425140-G-A

Position:

chr1-43425140-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001365999.1(SZT2):c.2578G>A(p.Glu860Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00902 in 1,614,162 control chromosomes in the GnomAD database, including 192 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0097 ( 21 hom., cov: 32)

Exomes 𝑓: 0.0089 ( 171 hom. )

Consequence

SZT2
NM_001365999.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.93

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 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=0.0014998913).

BP6

Variant 1-43425140-G-A is Benign according to our data. Variant chr1-43425140-G-A is described in ClinVar as [Benign]. Clinvar id is 241030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43425140-G-A is described in Lovd as [Benign]. Variant chr1-43425140-G-A is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SZT2	NM_001365999.1 linkuse as main transcript	c.2578G>A	p.Glu860Lys	missense_variant	18/72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4 linkuse as main transcript	c.2578G>A	p.Glu860Lys	missense_variant	18/71		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3 linkuse as main transcript	c.2578G>A	p.Glu860Lys	missense_variant	18/72	5	NM_001365999.1	ENSP00000489255	P1	Q5T011-1
SZT2	ENST00000562955.2 linkuse as main transcript	c.2578G>A	p.Glu860Lys	missense_variant	18/71	5		ENSP00000457168		Q5T011-5
SZT2	ENST00000470139.1 linkuse as main transcript	c.1309G>A	p.Glu437Lys	missense_variant, NMD_transcript_variant	9/18	2		ENSP00000492726

Frequencies

GnomAD3 genomes

AF:

0.00967

AC:

1471

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00278

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0434

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00766

Gnomad FIN

AF:

0.00424

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00819

Gnomad OTH

AF:

0.0119

GnomAD3 exomes

AF:

0.0155

AC:

3909

AN:

251458

Hom.:

117

AF XY:

0.0135

AC XY:

1841

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.0744

Gnomad ASJ exome

AF:

0.00635

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00679

Gnomad FIN exome

AF:

0.00333

Gnomad NFE exome

AF:

0.00765

Gnomad OTH exome

AF:

0.0134

GnomAD4 exome

AF:

0.00895

AC:

13082

AN:

1461860

Hom.:

171

Cov.:

AF XY:

0.00877

AC XY:

6380

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00218

Gnomad4 AMR exome

AF:

0.0688

Gnomad4 ASJ exome

AF:

0.00624

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00726

Gnomad4 FIN exome

AF:

0.00339

Gnomad4 NFE exome

AF:

0.00757

Gnomad4 OTH exome

AF:

0.00833

GnomAD4 genome

AF:

0.00966

AC:

1471

AN:

152302

Hom.:

Cov.:

AF XY:

0.00964

AC XY:

718

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00277

Gnomad4 AMR

AF:

0.0435

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00725

Gnomad4 FIN

AF:

0.00424

Gnomad4 NFE

AF:

0.00819

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.00789

Hom.:

Bravo

AF:

0.0120

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.00756

AC:

ExAC

AF:

0.0137

AC:

1658

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00911

EpiControl

AF:

0.00931

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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

Apr 15, 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

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.037

T;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.71

T;T

MetaRNN

Benign

0.0015

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.1

.;N

Sift

Benign

0.17

.;T

Sift4G

Benign

0.75

T;T

Polyphen

0.0

.;B

Vest4

0.071

MPC

0.30

ClinPred

0.0029

GERP RS

1.2

Varity_R

0.027

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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