1-43398186-G-A

Variant names:

• chr1-43398186-G-A
• rs839761
• NM_001365999.1:c.28-4991G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001365999.1(SZT2):​c.28-4991G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 152,122 control chromosomes in the GnomAD database, including 10,157 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.36 (10157 hom., cov: 32)
• Consequence: SZT2 NM_001365999.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.271
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365999.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SZT2	NM_001365999.1	MANE Select	c.28-4991G>A		intron	N/A	NP_001352928.1
	SZT2	NM_015284.4		c.28-4991G>A		intron	N/A	NP_056099.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SZT2	ENST00000634258.3	TSL:5 MANE Select	c.28-4991G>A		intron	N/A	ENSP00000489255.1
	SZT2	ENST00000372450.8	TSL:1	c.28-4991G>A		intron	N/A	ENSP00000361528.4
	SZT2	ENST00000357658.4	TSL:1	n.46-4991G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54126 AN: 152004 Hom.: 10153 Cov.: 32

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.0995

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.407

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.356 AC: 54163 AN: 152122 Hom.: 10157 Cov.: 32 AF XY: 0.351 AC XY: 26090 AN XY: 74392

African (AFR) AF: 0.275 AC: 11408 AN: 41484

American (AMR) AF: 0.400 AC: 6117 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1479 AN: 3472

East Asian (EAS) AF: 0.0993 AC: 515 AN: 5186

South Asian (SAS) AF: 0.157 AC: 756 AN: 4824

European-Finnish (FIN) AF: 0.393 AC: 4151 AN: 10566

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.417 AC: 28352 AN: 67986

Other (OTH) AF: 0.405 AC: 857 AN: 2116

Alfa AF: 0.379 Hom.: 1439

Bravo AF: 0.357

Asia WGS AF: 0.152 AC: 528 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.8
DANN	Benign	0.72
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs839761; hg19: chr1-43863857;