chr1-43441225-A-G

Position:

• chr1-43441225-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001365999.1(SZT2):​c.7356A>G​(p.Glu2452Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,613,758 control chromosomes in the GnomAD database, including 121,674 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8558 hom., cov: 32)
  • Exomes 𝑓: 0.38 (113116 hom.)
• Consequence: SZT2 NM_001365999.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.742

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-43441225-A-G is Benign according to our data. Variant chr1-43441225-A-G is described in ClinVar as [Benign]. Clinvar id is 260623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.742 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SZT2	NM_001365999.1	c.7356A>G	p.Glu2452Glu	synonymous_variant	53/72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4	c.7185A>G	p.Glu2395Glu	synonymous_variant	52/71		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3	c.7356A>G	p.Glu2452Glu	synonymous_variant	53/72	5	NM_001365999.1	ENSP00000489255.1
SZT2	ENST00000562955.2	c.7185A>G	p.Glu2395Glu	synonymous_variant	52/71	5		ENSP00000457168.1
SZT2	ENST00000648058.1	n.3810A>G		non_coding_transcript_exon_variant	21/40
SZT2	ENST00000649403.1	n.2106A>G		non_coding_transcript_exon_variant	18/37

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46734 AN: 152050 Hom.: 8558 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.0742

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.366

GnomAD3 exomes AF: 0.324 AC: 81444 AN: 251228 Hom.: 15371 AF XY: 0.324 AC XY: 43993 AN XY: 135782

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.437

Gnomad EAS exome AF: 0.0669

Gnomad SAS exome AF: 0.154

Gnomad FIN exome AF: 0.399

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.369

GnomAD4 exome AF: 0.382 AC: 558195 AN: 1461590 Hom.: 113116 Cov.: 51 AF XY: 0.376 AC XY: 273731 AN XY: 727074

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.333

Gnomad4 ASJ exome AF: 0.433

Gnomad4 EAS exome AF: 0.100

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.392

Gnomad4 NFE exome AF: 0.419

Gnomad4 OTH exome AF: 0.359

GnomAD4 genome AF: 0.307 AC: 46750 AN: 152168 Hom.: 8558 Cov.: 32 AF XY: 0.304 AC XY: 22609 AN XY: 74384

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.383

Gnomad4 ASJ AF: 0.425

Gnomad4 EAS AF: 0.0742

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.392

Gnomad4 NFE AF: 0.407

Gnomad4 OTH AF: 0.364

Alfa AF: 0.374 Hom.: 7185

Bravo AF: 0.302

Asia WGS AF: 0.128 AC: 444 AN: 3478

EpiCase AF: 0.418

EpiControl AF: 0.422

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Jan 08, 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	-0.74
CADD	Benign	10
DANN	Benign	0.60

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: rs2027130; hg19: chr1-43906896; COSMIC: COSV65169872; COSMIC: COSV65169872;