1-43424867-G-T

Variant names:

• chr1-43424867-G-T
• rs41270349
• NM_001365999.1:c.2550+5G>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.2550+5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,613,440 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (13 hom., cov: 32)
  • Exomes 𝑓: 0.014 (183 hom.)
• Consequence: SZT2 NM_001365999.1 splice_region, intron
• Scores: Splicing: ADA: 0.8143
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.78
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-43424867-G-T is Benign according to our data. Variant chr1-43424867-G-T is described in ClinVar as Benign. ClinVar VariationId is 260614.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 = 0.0103 (1569/152234) while in subpopulation NFE AF = 0.0147 (997/68012). AF 95% confidence interval is 0.0139. There are 13 homozygotes in GnomAd4. There are 758 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.2550+5G>T		splice_region intron	N/A	NP_001352928.1
	SZT2	NM_015284.4		c.2550+5G>T		splice_region 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.2550+5G>T		splice_region intron	N/A	ENSP00000489255.1
	SZT2	ENST00000562955.2	TSL:5	c.2550+5G>T		splice_region intron	N/A	ENSP00000457168.1
	SZT2	ENST00000470139.1	TSL:2	n.1281+5G>T		splice_region intron	N/A	ENSP00000492726.1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1563 AN: 152116 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00570

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0104 AC: 2615 AN: 251346 AF XY: 0.0109

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.00663

Gnomad ASJ exome AF: 0.00477

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00411

Gnomad NFE exome AF: 0.0154

Gnomad OTH exome AF: 0.00962

GnomAD4 exome AF: 0.0141 AC: 20652 AN: 1461206 Hom.: 183 Cov.: 32 AF XY: 0.0139 AC XY: 10088 AN XY: 726916

African (AFR) AF: 0.00529 AC: 177 AN: 33472

American (AMR) AF: 0.00765 AC: 342 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00471 AC: 123 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.0115 AC: 994 AN: 86248

European-Finnish (FIN) AF: 0.00610 AC: 326 AN: 53420

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5762

European-Non Finnish (NFE) AF: 0.0161 AC: 17852 AN: 1111412

Other (OTH) AF: 0.0128 AC: 775 AN: 60360

GnomAD4 genome AF: 0.0103 AC: 1569 AN: 152234 Hom.: 13 Cov.: 32 AF XY: 0.0102 AC XY: 758 AN XY: 74450

African (AFR) AF: 0.00580 AC: 241 AN: 41518

American (AMR) AF: 0.0126 AC: 193 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4818

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10620

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0147 AC: 997 AN: 68012

Other (OTH) AF: 0.0132 AC: 28 AN: 2116

Alfa AF: 0.00832 Hom.: 1

Bravo AF: 0.0103

EpiCase AF: 0.0128

EpiControl AF: 0.0144

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	17
DANN	Benign	0.60
PhyloP100		2.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.81
dbscSNV1_RF	Benign	0.57
SpliceAI score (max)		0.020		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: rs41270349; hg19: chr1-43890538;