rs139486476

Positions:

• chr1-43441565-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365999.1(SZT2):​c.7573G>A​(p.Val2525Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,614,176 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2525G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0065 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (15 hom.)
• Consequence: SZT2 NM_001365999.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.31

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]

ACMG classification

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=0.0036810935).
• BP6: Variant 1-43441565-G-A is Benign according to our data. Variant chr1-43441565-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 416970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43441565-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00652 (993/152290) while in subpopulation AFR AF= 0.0226 (941/41564). AF 95% confidence interval is 0.0214. There are 9 homozygotes in gnomad4. There are 487 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SZT2	NM_001365999.1	c.7573G>A	p.Val2525Ile	missense_variant	54/72	ENST00000634258.3
SZT2	NM_015284.4	c.7402G>A	p.Val2468Ile	missense_variant	53/71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SZT2	ENST00000634258.3	c.7573G>A	p.Val2525Ile	missense_variant	54/72	5	NM_001365999.1	P1
SZT2	ENST00000562955.2	c.7402G>A	p.Val2468Ile	missense_variant	53/71	5
SZT2	ENST00000648058.1	n.4027G>A		non_coding_transcript_exon_variant	22/40
SZT2	ENST00000649403.1	n.2323G>A		non_coding_transcript_exon_variant	19/37

Frequencies

GnomAD3 genomes AF: 0.00652 AC: 992 AN: 152172 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

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: 0.000103

Gnomad OTH AF: 0.00576

GnomAD3 exomes AF: 0.00173 AC: 434 AN: 251412 Hom.: 5 AF XY: 0.00132 AC XY: 179 AN XY: 135866

Gnomad AFR exome AF: 0.0238

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000634 AC: 927 AN: 1461886 Hom.: 15 Cov.: 52 AF XY: 0.000550 AC XY: 400 AN XY: 727248

Gnomad4 AFR exome AF: 0.0225

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.00652 AC: 993 AN: 152290 Hom.: 9 Cov.: 32 AF XY: 0.00654 AC XY: 487 AN XY: 74466

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00570

Alfa AF: 0.00125 Hom.: 4

Bravo AF: 0.00753

ESP6500AA AF: 0.0268 AC: 118

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00218 AC: 265

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 14, 2018	- -

Developmental and epileptic encephalopathy, 18 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 23, 2018

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	0.092
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.1
DANN	Benign	0.87
DEOGEN2	Benign	0.064	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0037	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.36	.;N
Sift	Benign	1.0	.;T
Sift4G	Benign	0.068	T;T
Polyphen		0.0010	.;B
Vest4		0.14
MVP		0.072
MPC		0.30
ClinPred		0.0059	T
GERP RS		0.33
Varity_R		0.013
gMVP		0.27

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

Other links and lift over

dbSNP: rs139486476; hg19: chr1-43907236;