rs72637949

Positions:

chr1-43440498-G-A

Variant summary

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

The NM_001365999.1(SZT2):c.7256G>A(p.Arg2419Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000798 in 1,608,082 control chromosomes in the GnomAD database, including 12 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 9 hom. )

Consequence

SZT2
NM_001365999.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.964

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:

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=0.0019628406).

BP6

Variant 1-43440498-G-A is Benign according to our data. Variant chr1-43440498-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 416972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43440498-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0014 (213/152256) while in subpopulation EAS AF= 0.0257 (133/5184). AF 95% confidence interval is 0.0221. There are 3 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SZT2	NM_001365999.1 linkuse as main transcript	c.7256G>A	p.Arg2419Gln	missense_variant	52/72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4 linkuse as main transcript	c.7085G>A	p.Arg2362Gln	missense_variant	51/71		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3 linkuse as main transcript	c.7256G>A	p.Arg2419Gln	missense_variant	52/72	5	NM_001365999.1	ENSP00000489255	P1	Q5T011-1
SZT2	ENST00000562955.2 linkuse as main transcript	c.7085G>A	p.Arg2362Gln	missense_variant	51/71	5		ENSP00000457168		Q5T011-5
SZT2	ENST00000648058.1 linkuse as main transcript	n.3710G>A		non_coding_transcript_exon_variant	20/40
SZT2	ENST00000649403.1 linkuse as main transcript	n.2006G>A		non_coding_transcript_exon_variant	17/37

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

214

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0256

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.00247

AC:

607

AN:

245502

Hom.:

AF XY:

0.00221

AC XY:

294

AN XY:

132916

show subpopulations

Gnomad AFR exome

AF:

0.00120

Gnomad AMR exome

AF:

0.00218

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.0271

Gnomad SAS exome

AF:

0.00107

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000269

Gnomad OTH exome

AF:

0.00118

GnomAD4 exome

AF:

0.000735

AC:

1070

AN:

1455826

Hom.:

Cov.:

AF XY:

0.000737

AC XY:

534

AN XY:

724190

show subpopulations

Gnomad4 AFR exome

AF:

0.000483

Gnomad4 AMR exome

AF:

0.00196

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.0184

Gnomad4 SAS exome

AF:

0.00134

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000379

Gnomad4 OTH exome

AF:

0.00158

GnomAD4 genome

AF:

0.00140

AC:

213

AN:

152256

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000963

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0257

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.00172

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00243

AC:

295

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.000388

EpiControl

AF:

0.000121

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 18

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.031

T;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.13

.;N

Sift

Benign

0.18

.;T

Sift4G

Benign

0.20

T;T

Polyphen

0.0

.;B

Vest4

0.14

MVP

0.16

MPC

0.60

ClinPred

0.015

GERP RS

-1.5

Varity_R

0.064

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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