1-43442603-C-T

Position:

• chr1-43442603-C-T

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.8136C>T​(p.Pro2712=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,604,230 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (18 hom.)
• Consequence: SZT2 NM_001365999.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.39

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=-0.87).
• BP6: Variant 1-43442603-C-T is Benign according to our data. Variant chr1-43442603-C-T is described in ClinVar as [Benign]. Clinvar id is 241038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.39 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0015 (229/152294) while in subpopulation EAS AF= 0.0398 (206/5180). AF 95% confidence interval is 0.0353. There are 9 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SZT2	NM_001365999.1	c.8136C>T	p.Pro2712=	synonymous_variant	58/72	ENST00000634258.3
SZT2	NM_015284.4	c.7965C>T	p.Pro2655=	synonymous_variant	57/71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SZT2	ENST00000634258.3	c.8136C>T	p.Pro2712=	synonymous_variant	58/72	5	NM_001365999.1	P1
SZT2	ENST00000562955.2	c.7965C>T	p.Pro2655=	synonymous_variant	57/71	5
SZT2	ENST00000648058.1	n.4590C>T		non_coding_transcript_exon_variant	26/40
SZT2	ENST00000649403.1	n.2886C>T		non_coding_transcript_exon_variant	23/37

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 230 AN: 152176 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0399

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00367 AC: 906 AN: 246552 Hom.: 18 AF XY: 0.00351 AC XY: 467 AN XY: 133194

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0464

Gnomad SAS exome AF: 0.000939

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000807

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.00103 AC: 1490 AN: 1451936 Hom.: 18 Cov.: 36 AF XY: 0.00103 AC XY: 740 AN XY: 720628

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.0000904

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0315

Gnomad4 SAS exome AF: 0.000959

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000308

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00150 AC: 229 AN: 152294 Hom.: 9 Cov.: 32 AF XY: 0.00184 AC XY: 137 AN XY: 74470

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0398

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000152 Hom.: 0

Bravo AF: 0.00213

Asia WGS AF: 0.0190 AC: 65 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	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2019	- -

Developmental and epileptic encephalopathy, 18 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 20, 2017

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2017

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	-0.87
CADD	Benign	0.49
DANN	Benign	0.55

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: rs2275098; hg19: chr1-43908274;