rs1889586

Positions:

• chr1-43416088-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001365999.1(SZT2):​c.759G>A​(p.Ser253=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,598,296 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (11 hom.)
• Consequence: SZT2 NM_001365999.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.289

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 -16 ACMG points.

• BP6: Variant 1-43416088-G-A is Benign according to our data. Variant chr1-43416088-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 416979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43416088-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00704 (1071/152232) while in subpopulation AFR AF= 0.0241 (1001/41518). AF 95% confidence interval is 0.0229. There are 12 homozygotes in gnomad4. There are 484 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SZT2	NM_001365999.1	c.759G>A	p.Ser253=	synonymous_variant	6/72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4	c.759G>A	p.Ser253=	synonymous_variant	6/71		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3	c.759G>A	p.Ser253=	synonymous_variant	6/72	5	NM_001365999.1	ENSP00000489255	P1
SZT2	ENST00000562955.2	c.759G>A	p.Ser253=	synonymous_variant	6/71	5		ENSP00000457168
SZT2	ENST00000639852.1	c.408G>A	p.Ser136=	synonymous_variant, NMD_transcript_variant	3/9	5		ENSP00000492385

Frequencies

GnomAD3 genomes AF: 0.00700 AC: 1065 AN: 152114 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00187 AC: 429 AN: 229002 Hom.: 3 AF XY: 0.00140 AC XY: 177 AN XY: 126562

Gnomad AFR exome AF: 0.0265

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.000740

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000284

Gnomad OTH exome AF: 0.000856

GnomAD4 exome AF: 0.000753 AC: 1089 AN: 1446064 Hom.: 11 Cov.: 31 AF XY: 0.000670 AC XY: 482 AN XY: 719748

Gnomad4 AFR exome AF: 0.0251

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000630

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.00158

GnomAD4 genome AF: 0.00704 AC: 1071 AN: 152232 Hom.: 12 Cov.: 32 AF XY: 0.00650 AC XY: 484 AN XY: 74430

Gnomad4 AFR AF: 0.0241

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00455 Hom.: 1

Bravo AF: 0.00816

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 05, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Developmental and epileptic encephalopathy, 18 Benign:1

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

Mar 18, 2016

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
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.5
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: 13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1889586; hg19: chr1-43881759;