chr1-43433166-G-T

Position:

• chr1-43433166-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001365999.1(SZT2):​c.5780G>T​(p.Arg1927Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,548 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1927C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SZT2 NM_001365999.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.97

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SZT2	NM_001365999.1	c.5780G>T	p.Arg1927Leu	missense_variant	40/72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4	c.5609G>T	p.Arg1870Leu	missense_variant	39/71		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3	c.5780G>T	p.Arg1927Leu	missense_variant	40/72	5	NM_001365999.1	ENSP00000489255.1
SZT2	ENST00000562955.2	c.5609G>T	p.Arg1870Leu	missense_variant	39/71	5		ENSP00000457168.1
SZT2	ENST00000648058.1	n.1039G>T		non_coding_transcript_exon_variant	9/40
SZT2	ENST00000649403.1	n.530G>T		non_coding_transcript_exon_variant	5/37

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251194 Hom.: 0 AF XY: 0.0000737 AC XY: 10 AN XY: 135770

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461548 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 29, 2019

In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is present in population databases (rs375009349, ExAC 0.04%) but has not been reported in the literature in individuals with a SZT2-related disease. This sequence change replaces arginine with leucine at codon 1870 of the SZT2 protein (p.Arg1870Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.0075	T
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.6	.;D
Sift	Benign	0.30	.;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.73
MutPred		0.55		.;Loss of loop (P = 0.0153);
MVP		0.54
MPC		0.61
ClinPred		0.44	T
GERP RS		5.8
Varity_R		0.66
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375009349; hg19: chr1-43898837;