chr1-43428371-T-C

Position:

chr1-43428371-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.4051T>C(p.Trp1351Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,614,172 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00081 ( 14 hom. )

Consequence

SZT2
NM_001365999.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.54

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=0.0035063922).

BP6

Variant 1-43428371-T-C is Benign according to our data. Variant chr1-43428371-T-C is described in ClinVar as [Benign]. Clinvar id is 416954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00731 (1113/152280) while in subpopulation AFR AF= 0.0255 (1058/41544). AF 95% confidence interval is 0.0242. There are 10 homozygotes in gnomad4. There are 511 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SZT2	NM_001365999.1 linkuse as main transcript	c.4051T>C	p.Trp1351Arg	missense_variant	28/72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4 linkuse as main transcript	c.3880T>C	p.Trp1294Arg	missense_variant	27/71		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3 linkuse as main transcript	c.4051T>C	p.Trp1351Arg	missense_variant	28/72	5	NM_001365999.1	ENSP00000489255	P1	Q5T011-1
SZT2	ENST00000562955.2 linkuse as main transcript	c.3880T>C	p.Trp1294Arg	missense_variant	27/71	5		ENSP00000457168		Q5T011-5
SZT2	ENST00000470139.1 linkuse as main transcript	c.*1186T>C		3_prime_UTR_variant, NMD_transcript_variant	18/18	2		ENSP00000492726

Frequencies

GnomAD3 genomes

AF:

0.00728

AC:

1107

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0254

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00198

AC:

497

AN:

251492

Hom.:

AF XY:

0.00132

AC XY:

179

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0266

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.000805

AC:

1177

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000670

AC XY:

487

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0282

Gnomad4 AMR exome

AF:

0.00165

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.00210

GnomAD4 genome

AF:

0.00731

AC:

1113

AN:

152280

Hom.:

Cov.:

AF XY:

0.00686

AC XY:

511

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0255

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00170

Hom.:

Bravo

AF:

0.00847

ESP6500AA

AF:

0.0254

AC:

112

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00234

AC:

284

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 08, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Jan 18, 2017

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

0.10

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.029

T;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.43

T;T

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.41

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

0.89

.;N

Sift

Benign

0.84

.;T

Sift4G

Benign

0.90

T;T

Polyphen

0.0

.;B

Vest4

0.27

MutPred

0.33

.;Gain of disorder (P = 0.0078);

MVP

0.32

MPC

0.46

ClinPred

0.0014

GERP RS

3.3

Varity_R

0.070

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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