1-43438733-A-G

Variant names:

• chr1-43438733-A-G
• rs112461557
• NM_001365999.1:c.6543A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001365999.1(SZT2):​c.6543A>G​(p.Leu2181Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00627 in 1,614,064 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2181L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0050 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0064 (49 hom.)
• Consequence: SZT2 NM_001365999.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.11
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 1-43438733-A-G is Benign according to our data. Variant chr1-43438733-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00503 (765/152216) while in subpopulation NFE AF = 0.00704 (479/68006). AF 95% confidence interval is 0.00652. There are 5 homozygotes in GnomAd4. There are 373 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.6543A>G	p.Leu2181Leu	synonymous	Exon 47 of 72	NP_001352928.1
	SZT2	NM_015284.4		c.6372A>G	p.Leu2124Leu	synonymous	Exon 46 of 71	NP_056099.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SZT2	ENST00000634258.3	TSL:5 MANE Select	c.6543A>G	p.Leu2181Leu	synonymous	Exon 47 of 72	ENSP00000489255.1
	SZT2	ENST00000562955.2	TSL:5	c.6372A>G	p.Leu2124Leu	synonymous	Exon 46 of 71	ENSP00000457168.1
	SZT2	ENST00000471177.1	TSL:4	n.206A>G		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes AF: 0.00502 AC: 764 AN: 152098 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00704

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00528 AC: 1328 AN: 251348 AF XY: 0.00534

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0148

Gnomad NFE exome AF: 0.00724

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00640 AC: 9355 AN: 1461848 Hom.: 49 Cov.: 33 AF XY: 0.00622 AC XY: 4522 AN XY: 727224

African (AFR) AF: 0.000986 AC: 33 AN: 33480

American (AMR) AF: 0.00237 AC: 106 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 46 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00145 AC: 125 AN: 86254

European-Finnish (FIN) AF: 0.0143 AC: 766 AN: 53414

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.00719 AC: 7998 AN: 1111978

Other (OTH) AF: 0.00440 AC: 266 AN: 60396

GnomAD4 genome AF: 0.00503 AC: 765 AN: 152216 Hom.: 5 Cov.: 33 AF XY: 0.00501 AC XY: 373 AN XY: 74434

African (AFR) AF: 0.00154 AC: 64 AN: 41528

American (AMR) AF: 0.00281 AC: 43 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4820

European-Finnish (FIN) AF: 0.0151 AC: 160 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00704 AC: 479 AN: 68006

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00524 Hom.: 1

Bravo AF: 0.00437

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00616

EpiControl AF: 0.00634

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Developmental and epileptic encephalopathy, 18 (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.5
DANN	Benign	0.39
PhyloP100		2.1
Mutation Taster		=99/1	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: rs112461557; hg19: chr1-43904404; COSMIC: COSV65175290; COSMIC: COSV65175290;