1-43431066-C-T

Position:

• chr1-43431066-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_001365999.1(SZT2):​c.4892C>T​(p.Thr1631Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,613,896 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). Synonymous variant affecting the same amino acid position (i.e. T1631T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: SZT2 NM_001365999.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 3.10

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 (HGNC:):

ACMG classification

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=0.007987797).
• BP6: Variant 1-43431066-C-T is Benign according to our data. Variant chr1-43431066-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411931.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SZT2	NM_001365999.1	c.4892C>T	p.Thr1631Met	missense_variant	33/72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4	c.4721C>T	p.Thr1574Met	missense_variant	32/71		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3	c.4892C>T	p.Thr1631Met	missense_variant	33/72	5	NM_001365999.1	ENSP00000489255.1
SZT2	ENST00000562955.2	c.4721C>T	p.Thr1574Met	missense_variant	32/71	5		ENSP00000457168.1
SZT2	ENST00000648058.1	n.32C>T		non_coding_transcript_exon_variant	1/40

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000442 AC: 111 AN: 251138 Hom.: 0 AF XY: 0.000516 AC XY: 70 AN XY: 135744

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00258

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000242 AC: 354 AN: 1461664 Hom.: 2 Cov.: 32 AF XY: 0.000314 AC XY: 228 AN XY: 727142

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00209

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74430

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 18 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jun 16, 2021	SZT2 NM_015284.3 exon 32 p.Thr1574Met (c.4721C>T): This variant has not been reported in the literature but is present in 0.01% (11/68026) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-43431066-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:411931). This variant amino acid Methionine (Met) is present in >10 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2019

The p.T1574M variant (also known as c.4721C>T), located in coding exon 32 of the SZT2 gene, results from a C to T substitution at nucleotide position 4721. The threonine at codon 1574 is replaced by methionine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

SZT2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2022

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	0.072
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.034	T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.0080	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.16	.;N
Sift	Benign	0.12	.;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0030	.;B
Vest4		0.20
MVP		0.17
MPC		0.37
ClinPred		0.013	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.028
gMVP		0.32

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

Other links and lift over

dbSNP: rs201312287; hg19: chr1-43896737; COSMIC: COSV65170542; COSMIC: COSV65170542;