rs140366288

Variant names:

• chr1-43426818-C-T
• rs140366288
• NM_001365999.1:c.3309+9C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001365999.1(SZT2):​c.3309+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,612,260 control chromosomes in the GnomAD database, including 6 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: 0.0014 (6 hom.)
• Consequence: SZT2 NM_001365999.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -1.34
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Illumina
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-43426818-C-T is Benign according to our data. Variant chr1-43426818-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 416959.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SZT2	NM_001365999.1	MANE Select	c.3309+9C>T		intron	N/A	NP_001352928.1
	SZT2	NM_015284.4		c.3138+9C>T		intron	N/A	NP_056099.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SZT2	ENST00000634258.3	TSL:5 MANE Select	c.3309+9C>T		intron	N/A	ENSP00000489255.1
	SZT2	ENST00000562955.2	TSL:5	c.3138+9C>T		intron	N/A	ENSP00000457168.1
	SZT2	ENST00000470139.1	TSL:2	n.*176+9C>T		intron	N/A	ENSP00000492726.1

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000869 AC: 214 AN: 246276 AF XY: 0.000863

Gnomad AFR exome AF: 0.000377

Gnomad AMR exome AF: 0.000293

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000484

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.000501

GnomAD4 exome AF: 0.00143 AC: 2094 AN: 1459968 Hom.: 6 Cov.: 31 AF XY: 0.00140 AC XY: 1020 AN XY: 726216

African (AFR) AF: 0.000269 AC: 9 AN: 33462

American (AMR) AF: 0.000337 AC: 15 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.0000768 AC: 2 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.000686 AC: 59 AN: 86002

European-Finnish (FIN) AF: 0.000394 AC: 21 AN: 53354

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00172 AC: 1910 AN: 1110862

Other (OTH) AF: 0.00126 AC: 76 AN: 60322

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000859 AC XY: 64 AN XY: 74472

African (AFR) AF: 0.000265 AC: 11 AN: 41556

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00210 AC: 143 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00106

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.66
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140366288; hg19: chr1-43892489;