rs139810154

Positions:

• chr1-43431331-T-C

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.4983T>C​(p.Asp1661Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,613,458 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (7 hom.)
• Consequence: SZT2 NM_001365999.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.735

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=-0.53).
• BP6: Variant 1-43431331-T-C is Benign according to our data. Variant chr1-43431331-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 416955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43431331-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.735 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00117 (1705/1461192) while in subpopulation MID AF= 0.00937 (54/5764). AF 95% confidence interval is 0.00737. There are 7 homozygotes in gnomad4_exome. There are 935 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SZT2	NM_001365999.1	c.4983T>C	p.Asp1661Asp	synonymous_variant	34/72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4	c.4812T>C	p.Asp1604Asp	synonymous_variant	33/71		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3	c.4983T>C	p.Asp1661Asp	synonymous_variant	34/72	5	NM_001365999.1	ENSP00000489255.1
SZT2	ENST00000562955.2	c.4812T>C	p.Asp1604Asp	synonymous_variant	33/71	5		ENSP00000457168.1
SZT2	ENST00000638642.1	n.201T>C		non_coding_transcript_exon_variant	1/3	3
SZT2	ENST00000648058.1	n.123T>C		non_coding_transcript_exon_variant	2/40

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00154 AC: 386 AN: 250982 Hom.: 3 AF XY: 0.00182 AC XY: 247 AN XY: 135602

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00399

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00328

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00117 AC: 1705 AN: 1461192 Hom.: 7 Cov.: 32 AF XY: 0.00129 AC XY: 935 AN XY: 726824

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.00349

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00337

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000985

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74450

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00165 Hom.: 1

Bravo AF: 0.00129

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SZT2: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 25, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Developmental and epileptic encephalopathy, 18 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 15, 2021	- -
Likely 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

Jun 21, 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	-0.53
CADD	Benign	8.7
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs139810154; hg19: chr1-43897002;