1-43437918-G-T

Variant names:

• chr1-43437918-G-T
• rs2782648
• NM_001365999.1:c.6508+16G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365999.1(SZT2):​c.6508+16G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 1,613,306 control chromosomes in the GnomAD database, including 122,461 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8871 hom., cov: 32)
  • Exomes 𝑓: 0.38 (113590 hom.)
• Consequence: SZT2 NM_001365999.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.735
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 18

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Illumina
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-43437918-G-T is Benign according to our data. Variant chr1-43437918-G-T is described in ClinVar as Benign. ClinVar VariationId is 260620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SZT2	NM_001365999.1	c.6508+16G>T		intron_variant	Intron 46 of 71	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4	c.6337+16G>T		intron_variant	Intron 45 of 70		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3	c.6508+16G>T		intron_variant	Intron 46 of 71	5	NM_001365999.1	ENSP00000489255.1

Frequencies

GnomAD3 genomes AF: 0.323 AC: 48979 AN: 151834 Hom.: 8872 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.0735

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.436

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.378

GnomAD2 exomes AF: 0.328 AC: 82336 AN: 250836 AF XY: 0.327

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.436

Gnomad EAS exome AF: 0.0669

Gnomad FIN exome AF: 0.399

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.372

GnomAD4 exome AF: 0.384 AC: 560789 AN: 1461354 Hom.: 113590 Cov.: 34 AF XY: 0.378 AC XY: 274783 AN XY: 726974

African (AFR) AF: 0.179 AC: 5989 AN: 33470

American (AMR) AF: 0.335 AC: 15004 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 11317 AN: 26124

East Asian (EAS) AF: 0.100 AC: 3987 AN: 39698

South Asian (SAS) AF: 0.158 AC: 13596 AN: 86244

European-Finnish (FIN) AF: 0.392 AC: 20924 AN: 53324

Middle Eastern (MID) AF: 0.402 AC: 2317 AN: 5764

European-Non Finnish (NFE) AF: 0.419 AC: 465764 AN: 1111628

Other (OTH) AF: 0.363 AC: 21891 AN: 60378

GnomAD4 genome AF: 0.322 AC: 49002 AN: 151952 Hom.: 8871 Cov.: 32 AF XY: 0.318 AC XY: 23652 AN XY: 74276

African (AFR) AF: 0.180 AC: 7450 AN: 41456

American (AMR) AF: 0.387 AC: 5898 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1473 AN: 3466

East Asian (EAS) AF: 0.0734 AC: 380 AN: 5174

South Asian (SAS) AF: 0.147 AC: 706 AN: 4814

European-Finnish (FIN) AF: 0.391 AC: 4124 AN: 10540

Middle Eastern (MID) AF: 0.445 AC: 130 AN: 292

European-Non Finnish (NFE) AF: 0.407 AC: 27661 AN: 67926

Other (OTH) AF: 0.376 AC: 795 AN: 2114

Alfa AF: 0.318 Hom.: 1776

Bravo AF: 0.320

Asia WGS AF: 0.131 AC: 457 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Developmental and epileptic encephalopathy, 18 Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.21
DANN	Benign	0.26
PhyloP100		-0.73
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2782648; hg19: chr1-43903589;