1-43437684-A-T

Position:

chr1-43437684-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS1

The NM_001365999.1(SZT2):c.6380A>T(p.Tyr2127Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000386 in 1,613,352 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

SZT2
NM_001365999.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.684

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 Benign. Variant got -8 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=0.00518474).

BP6

Variant 1-43437684-A-T is Benign according to our data. Variant chr1-43437684-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212366.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00184 (279/151500) while in subpopulation AFR AF= 0.00616 (254/41238). AF 95% confidence interval is 0.00554. There are 1 homozygotes in gnomad4. There are 137 alleles in male gnomad4 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.6380A>T	p.Tyr2127Phe	missense_variant	45/72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4 linkuse as main transcript	c.6209A>T	p.Tyr2070Phe	missense_variant	44/71		NP_056099.3	Q5T011-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3 linkuse as main transcript	c.6380A>T	p.Tyr2127Phe	missense_variant	45/72	5	NM_001365999.1	ENSP00000489255.1		Q5T011-1

Frequencies

GnomAD3 genomes

AF:

0.00184

AC:

279

AN:

151380

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00618

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00125

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00145

GnomAD3 exomes

AF:

0.000513

AC:

129

AN:

251304

Hom.:

AF XY:

0.000346

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.00610

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000235

AC:

343

AN:

1461852

Hom.:

Cov.:

AF XY:

0.000217

AC XY:

158

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00660

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000567

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.00184

AC:

279

AN:

151500

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

137

AN XY:

74016

show subpopulations

Gnomad4 AFR

AF:

0.00616

Gnomad4 AMR

AF:

0.00125

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.000317

Hom.:

Bravo

AF:

0.00195

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000593

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	SZT2: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 08, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 06, 2015	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

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. -

SZT2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 23, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.2

DANN

Benign

0.80

DEOGEN2

Benign

0.041

T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.0035

MetaRNN

Benign

0.0052

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.57

.;N

Sift

Benign

0.69

.;T

Sift4G

Benign

0.69

T;T

Polyphen

0.0010

.;B

Vest4

0.27

MVP

0.12

MPC

0.24

ClinPred

0.00090

GERP RS

-2.7

Varity_R

0.044

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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