Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000634258.3(SZT2):c.4618G>A(p.Asp1540Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1540V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SZT2
ENST00000634258.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.42

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 18
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Illumina
genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SZT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000634258.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SZT2	NM_001365999.1	MANE Select	c.4618G>A	p.Asp1540Asn	missense	Exon 32 of 72	NP_001352928.1
	SZT2	NM_015284.4		c.4447G>A	p.Asp1483Asn	missense	Exon 31 of 71	NP_056099.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SZT2	ENST00000634258.3	TSL:5 MANE Select	c.4618G>A	p.Asp1540Asn	missense	Exon 32 of 72	ENSP00000489255.1
SZT2	ENST00000562955.2	TSL:5	c.4447G>A	p.Asp1483Asn	missense	Exon 31 of 71	ENSP00000457168.1
SZT2	ENST00000478140.1	TSL:2	n.479G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.011

MetaRNN

Benign

0.37

MetaSVM

Benign

-0.29

MutationAssessor

Benign

2.0

PhyloP100

9.4

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-2.3

Sift

Uncertain

0.019

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.53

MutPred

0.35

Gain of sheet (P = 0.0827)

MVP

0.32

MPC

0.92

ClinPred

0.87

GERP RS

5.8

Varity_R

0.43

gMVP

0.51

Mutation Taster

=58/42

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.28

Position offset: 17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs1057520164

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over