rs72637949

chr1-43440498-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.7256G>A(p.Arg2419Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000798 in 1,608,082 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (9 hom.)
• Consequence: SZT2 NM_001365999.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.964

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 where missense usually causes diseases, SZT2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0019628406).
• BP6: Variant 1-43440498-G-A is Benign according to our data. Variant chr1-43440498-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 416972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43440498-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0014 (213/152256) while in subpopulation EAS AF= 0.0257 (133/5184). AF 95% confidence interval is 0.0221. There are 3 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SZT2	NM_001365999.1	c.7256G>A	p.Arg2419Gln	missense_variant	52/72	ENST00000634258.3
SZT2	NM_015284.4	c.7085G>A	p.Arg2362Gln	missense_variant	51/71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SZT2	ENST00000634258.3	c.7256G>A	p.Arg2419Gln	missense_variant	52/72	5	NM_001365999.1	P1
SZT2	ENST00000562955.2	c.7085G>A	p.Arg2362Gln	missense_variant	51/71	5
SZT2	ENST00000648058.1	n.3710G>A		non_coding_transcript_exon_variant	20/40
SZT2	ENST00000649403.1	n.2006G>A		non_coding_transcript_exon_variant	17/37

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 152138 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00247 AC: 607 AN: 245502 Hom.: 7 AF XY: 0.00221 AC XY: 294 AN XY: 132916

Gnomad AFR exome AF: 0.00120

Gnomad AMR exome AF: 0.00218

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0271

Gnomad SAS exome AF: 0.00107

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.000735 AC: 1070 AN: 1455826 Hom.: 9 Cov.: 31 AF XY: 0.000737 AC XY: 534 AN XY: 724190

Gnomad4 AFR exome AF: 0.000483

Gnomad4 AMR exome AF: 0.00196

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.0184

Gnomad4 SAS exome AF: 0.00134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000379

Gnomad4 OTH exome AF: 0.00158

GnomAD4 genome AF: 0.00140 AC: 213 AN: 152256 Hom.: 3 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74452

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0257

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00114 Hom.: 5

Bravo AF: 0.00172

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00243 AC: 295

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000388

EpiControl AF: 0.000121

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 18 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2017

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	0.074
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.031	T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
Sift4G	Benign	0.20	T;T
Polyphen		0.0	.;B
Vest4		0.14
MVP		0.16
MPC		0.60
ClinPred		0.015	T
GERP RS		-1.5
Varity_R		0.064
gMVP		0.25

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: rs72637949; hg19: chr1-43906169;