rs2782643

Variant names:

• chr1-43420823-C-T
• rs2782643
• NM_001365999.1:c.1336C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-43420823-C-T
• chr1-43420823-C-A
• chr1-43420823-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365999.1(SZT2):​c.1336C>T​(p.Pro446Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,598,182 control chromosomes in the GnomAD database, including 120,395 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P446P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.31 (8579 hom., cov: 32)
  • Exomes 𝑓: 0.38 (111816 hom.)
• Consequence: SZT2 NM_001365999.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.45
• Publications: 34 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=0.0023969412).
• BP6: Variant 1-43420823-C-T is Benign according to our data. Variant chr1-43420823-C-T is described in ClinVar as Benign. ClinVar VariationId is 260613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

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.1336C>T	p.Pro446Ser	missense	Exon 10 of 72	NP_001352928.1	Q5T011-1
	SZT2	NM_015284.4		c.1336C>T	p.Pro446Ser	missense	Exon 10 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.1336C>T	p.Pro446Ser	missense	Exon 10 of 72	ENSP00000489255.1	Q5T011-1
	SZT2	ENST00000562955.2	TSL:5	c.1336C>T	p.Pro446Ser	missense	Exon 10 of 71	ENSP00000457168.1	Q5T011-5
	SZT2	ENST00000470139.1	TSL:2	n.67C>T		non_coding_transcript_exon	Exon 1 of 18	ENSP00000492726.1	A0A1W2PRY5

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47276 AN: 151952 Hom.: 8581 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.0730

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.370

GnomAD2 exomes AF: 0.321 AC: 73724 AN: 229432 AF XY: 0.321

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.322

Gnomad ASJ exome AF: 0.438

Gnomad EAS exome AF: 0.0657

Gnomad FIN exome AF: 0.402

Gnomad NFE exome AF: 0.414

Gnomad OTH exome AF: 0.367

GnomAD4 exome AF: 0.382 AC: 552275 AN: 1446112 Hom.: 111816 Cov.: 67 AF XY: 0.376 AC XY: 270826 AN XY: 719778

African (AFR) AF: 0.136 AC: 4557 AN: 33474

American (AMR) AF: 0.332 AC: 14847 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 11312 AN: 26134

East Asian (EAS) AF: 0.100 AC: 3987 AN: 39696

South Asian (SAS) AF: 0.157 AC: 13525 AN: 86258

European-Finnish (FIN) AF: 0.392 AC: 14916 AN: 38026

Middle Eastern (MID) AF: 0.396 AC: 2285 AN: 5766

European-Non Finnish (NFE) AF: 0.418 AC: 465189 AN: 1111762

Other (OTH) AF: 0.359 AC: 21657 AN: 60276

GnomAD4 genome AF: 0.311 AC: 47295 AN: 152070 Hom.: 8579 Cov.: 32 AF XY: 0.307 AC XY: 22834 AN XY: 74324

African (AFR) AF: 0.141 AC: 5844 AN: 41512

American (AMR) AF: 0.380 AC: 5804 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1473 AN: 3470

East Asian (EAS) AF: 0.0730 AC: 378 AN: 5178

South Asian (SAS) AF: 0.146 AC: 704 AN: 4822

European-Finnish (FIN) AF: 0.393 AC: 4144 AN: 10544

Middle Eastern (MID) AF: 0.438 AC: 128 AN: 292

European-Non Finnish (NFE) AF: 0.407 AC: 27657 AN: 67952

Other (OTH) AF: 0.368 AC: 776 AN: 2108

Alfa AF: 0.375 Hom.: 49771

Bravo AF: 0.306

TwinsUK AF: 0.419 AC: 1555

ALSPAC AF: 0.417 AC: 1609

ESP6500AA AF: 0.146 AC: 256

ESP6500EA AF: 0.424 AC: 1687

ExAC AF: 0.316 AC: 36351

Asia WGS AF: 0.129 AC: 450 AN: 3478

EpiCase AF: 0.417

EpiControl AF: 0.421

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Developmental and epileptic encephalopathy, 18 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.095	T
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0024	T
MutationAssessor	Benign	0.14	N
PhyloP100		1.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.8	N
Sift	Benign	0.19	T
Sift4G	Benign	0.57	T
Vest4		0.074
MPC		1.3
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.89
Mutation Taster		=71/29	polymorphism (auto)

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: rs2782643; hg19: chr1-43886494; COSMIC: COSV65168240;