rs12129487

Positions:

• chr1-43432382-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001365999.1(SZT2):​c.5385T>G​(p.Ser1795=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,600,920 control chromosomes in the GnomAD database, including 772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (101 hom., cov: 32)
  • Exomes 𝑓: 0.029 (671 hom.)
• Consequence: SZT2 NM_001365999.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.589

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-43432382-T-G is Benign according to our data. Variant chr1-43432382-T-G is described in ClinVar as [Benign]. Clinvar id is 260617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43432382-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.589 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0314 (4784/152272) while in subpopulation SAS AF= 0.0479 (231/4820). AF 95% confidence interval is 0.0429. There are 101 homozygotes in gnomad4. There are 2358 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 101 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SZT2	NM_001365999.1	c.5385T>G	p.Ser1795=	synonymous_variant	37/72	ENST00000634258.3
SZT2	NM_015284.4	c.5214T>G	p.Ser1738=	synonymous_variant	36/71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SZT2	ENST00000634258.3	c.5385T>G	p.Ser1795=	synonymous_variant	37/72	5	NM_001365999.1	P1
SZT2	ENST00000562955.2	c.5214T>G	p.Ser1738=	synonymous_variant	36/71	5
SZT2	ENST00000648058.1	n.644T>G		non_coding_transcript_exon_variant	6/40
SZT2	ENST00000649403.1	n.135T>G		non_coding_transcript_exon_variant	2/37

Frequencies

GnomAD3 genomes AF: 0.0314 AC: 4782 AN: 152154 Hom.: 100 Cov.: 32

Gnomad AFR AF: 0.0404

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.0692

Gnomad EAS AF: 0.0194

Gnomad SAS AF: 0.0481

Gnomad FIN AF: 0.0236

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0272

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0295 AC: 6997 AN: 237500 Hom.: 109 AF XY: 0.0303 AC XY: 3891 AN XY: 128470

Gnomad AFR exome AF: 0.0393

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.0616

Gnomad EAS exome AF: 0.0230

Gnomad SAS exome AF: 0.0387

Gnomad FIN exome AF: 0.0259

Gnomad NFE exome AF: 0.0290

Gnomad OTH exome AF: 0.0300

GnomAD4 exome AF: 0.0287 AC: 41504 AN: 1448648 Hom.: 671 Cov.: 33 AF XY: 0.0291 AC XY: 20935 AN XY: 720130

Gnomad4 AFR exome AF: 0.0431

Gnomad4 AMR exome AF: 0.0161

Gnomad4 ASJ exome AF: 0.0620

Gnomad4 EAS exome AF: 0.0154

Gnomad4 SAS exome AF: 0.0402

Gnomad4 FIN exome AF: 0.0245

Gnomad4 NFE exome AF: 0.0276

Gnomad4 OTH exome AF: 0.0303

GnomAD4 genome AF: 0.0314 AC: 4784 AN: 152272 Hom.: 101 Cov.: 32 AF XY: 0.0317 AC XY: 2358 AN XY: 74456

Gnomad4 AFR AF: 0.0404

Gnomad4 AMR AF: 0.0205

Gnomad4 ASJ AF: 0.0692

Gnomad4 EAS AF: 0.0195

Gnomad4 SAS AF: 0.0479

Gnomad4 FIN AF: 0.0236

Gnomad4 NFE AF: 0.0272

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0297 Hom.: 59

Bravo AF: 0.0313

Asia WGS AF: 0.0240 AC: 82 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2016

This alteration is classified as 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	-0.83
CADD	Benign	7.9
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs12129487; hg19: chr1-43898053; COSMIC: COSV65169863; COSMIC: COSV65169863;