rs143185010

Positions:

chr1-43432374-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM2PP2BP4_ModerateBP6BS1

The NM_001365999.1(SZT2):c.5377G>A(p.Glu1793Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000133 in 1,604,894 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E1793E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

SZT2
NM_001365999.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 4.75

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 Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.07878429).

BP6

Variant 1-43432374-G-A is Benign according to our data. Variant chr1-43432374-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411946.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}. Variant chr1-43432374-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000137 (199/1452608) while in subpopulation MID AF= 0.00456 (26/5696). AF 95% confidence interval is 0.0032. There are 0 homozygotes in gnomad4_exome. There are 113 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SZT2	NM_001365999.1 linkuse as main transcript	c.5377G>A	p.Glu1793Lys	missense_variant	37/72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4 linkuse as main transcript	c.5206G>A	p.Glu1736Lys	missense_variant	36/71		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.5377G>A	p.Glu1793Lys	missense_variant	37/72	5	NM_001365999.1	ENSP00000489255.1	Q5T011-1
SZT2	ENST00000562955.2 linkuse as main transcript	c.5206G>A	p.Glu1736Lys	missense_variant	36/71	5		ENSP00000457168.1	Q5T011-5
SZT2	ENST00000648058.1 linkuse as main transcript	n.636G>A		non_coding_transcript_exon_variant	6/40
SZT2	ENST00000649403.1 linkuse as main transcript	n.127G>A		non_coding_transcript_exon_variant	2/37

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000208

AC:

AN:

240226

Hom.:

AF XY:

0.000231

AC XY:

AN XY:

129976

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000309

Gnomad ASJ exome

AF:

0.000109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000486

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000192

Gnomad OTH exome

AF:

0.000697

GnomAD4 exome

AF:

0.000137

AC:

199

AN:

1452608

Hom.:

Cov.:

AF XY:

0.000156

AC XY:

113

AN XY:

722202

show subpopulations

Gnomad4 AFR exome

AF:

0.000242

Gnomad4 AMR exome

AF:

0.000233

Gnomad4 ASJ exome

AF:

0.0000394

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000271

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000104

Gnomad4 OTH exome

AF:

0.000267

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000171

Hom.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000255

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 20, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2018	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2021

The c.5206G>A (p.E1736K) alteration is located in exon 36 (coding exon 36) of the SZT2 gene. This alteration results from a G to A substitution at nucleotide position 5206, causing the glutamic acid (E) at amino acid position 1736 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.060

T;.

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.0063

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.079

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

N;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.4

.;N

Sift

Uncertain

0.011

.;D

Sift4G

Benign

0.46

T;T

Polyphen

0.23

.;B

Vest4

0.28

MVP

0.30

MPC

0.31

ClinPred

0.046

GERP RS

5.8

Varity_R

0.11

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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