rs76675748

Variant names:

• chr1-43430546-G-A
• rs76675748
• NM_001365999.1:c.4531G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-43430546-G-A
• chr1-43430546-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365999.1(SZT2):​c.4531G>A​(p.Val1511Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,614,228 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1511A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (38 hom.)
• Consequence: SZT2 NM_001365999.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 9.42
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 18

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, PanelApp Australia
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008562744).
• BP6: Variant 1-43430546-G-A is Benign according to our data. Variant chr1-43430546-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00356 (542/152342) while in subpopulation NFE AF = 0.00607 (413/68030). AF 95% confidence interval is 0.00559. There are 1 homozygotes in GnomAd4. There are 267 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 38 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365999.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SZT2	NM_001365999.1	MANE Select	c.4531G>A	p.Val1511Ile	missense	Exon 32 of 72	NP_001352928.1	Q5T011-1
	SZT2	NM_015284.4		c.4360G>A	p.Val1454Ile	missense	Exon 31 of 71	NP_056099.3	Q5T011-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SZT2	ENST00000634258.3	TSL:5 MANE Select	c.4531G>A	p.Val1511Ile	missense	Exon 32 of 72	ENSP00000489255.1	Q5T011-1
	SZT2	ENST00000562955.2	TSL:5	c.4360G>A	p.Val1454Ile	missense	Exon 31 of 71	ENSP00000457168.1	Q5T011-5
	SZT2	ENST00000478140.1	TSL:2	n.392G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00356 AC: 542 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00607

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00353 AC: 888 AN: 251426 AF XY: 0.00353

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00577

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00515 AC: 7525 AN: 1461886 Hom.: 38 Cov.: 33 AF XY: 0.00503 AC XY: 3661 AN XY: 727246

African (AFR) AF: 0.000926 AC: 31 AN: 33480

American (AMR) AF: 0.00286 AC: 128 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 38 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00225 AC: 194 AN: 86256

European-Finnish (FIN) AF: 0.000374 AC: 20 AN: 53418

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.00616 AC: 6855 AN: 1112008

Other (OTH) AF: 0.00374 AC: 226 AN: 60396

GnomAD4 genome AF: 0.00356 AC: 542 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00358 AC XY: 267 AN XY: 74494

African (AFR) AF: 0.00106 AC: 44 AN: 41578

American (AMR) AF: 0.00340 AC: 52 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00607 AC: 413 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00494 Hom.: 3

Bravo AF: 0.00365

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00349 AC: 424

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00522

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	Developmental and epileptic encephalopathy, 18 (3)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	SZT2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	2.0	M
PhyloP100		9.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.38	N
Sift	Benign	0.13	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.39
MVP		0.37
MPC		0.83
ClinPred		0.028	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.22
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs76675748; hg19: chr1-43896217;