chr1-43425193-C-T

Variant names:

• chr1-43425193-C-T
• rs140831372
• NM_001365999.1:c.2631C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001365999.1(SZT2):​c.2631C>T​(p.Thr877Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00898 in 1,614,192 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0092 (81 hom.)
• Consequence: SZT2 NM_001365999.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0910
• Publications: 4 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 1-43425193-C-T is Benign according to our data. Variant chr1-43425193-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.091 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0071 (1082/152340) while in subpopulation NFE AF = 0.0103 (702/68030). AF 95% confidence interval is 0.00969. There are 7 homozygotes in GnomAd4. There are 521 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.2631C>T	p.Thr877Thr	synonymous	Exon 18 of 72	NP_001352928.1	Q5T011-1
	SZT2	NM_015284.4		c.2631C>T	p.Thr877Thr	synonymous	Exon 18 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.2631C>T	p.Thr877Thr	synonymous	Exon 18 of 72	ENSP00000489255.1	Q5T011-1
	SZT2	ENST00000562955.2	TSL:5	c.2631C>T	p.Thr877Thr	synonymous	Exon 18 of 71	ENSP00000457168.1	Q5T011-5
	SZT2	ENST00000470139.1	TSL:2	n.1362C>T		non_coding_transcript_exon	Exon 9 of 18	ENSP00000492726.1	A0A1W2PRY5

Frequencies

GnomAD3 genomes AF: 0.00708 AC: 1078 AN: 152222 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00754 AC: 1894 AN: 251308 AF XY: 0.00712

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.0166

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00910

Gnomad NFE exome AF: 0.00796

Gnomad OTH exome AF: 0.00961

GnomAD4 exome AF: 0.00917 AC: 13408 AN: 1461852 Hom.: 81 Cov.: 32 AF XY: 0.00898 AC XY: 6527 AN XY: 727234

African (AFR) AF: 0.00137 AC: 46 AN: 33480

American (AMR) AF: 0.0153 AC: 685 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

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

South Asian (SAS) AF: 0.00452 AC: 390 AN: 86250

European-Finnish (FIN) AF: 0.00936 AC: 500 AN: 53414

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.0101 AC: 11185 AN: 1111992

Other (OTH) AF: 0.00974 AC: 588 AN: 60394

GnomAD4 genome AF: 0.00710 AC: 1082 AN: 152340 Hom.: 7 Cov.: 32 AF XY: 0.00699 AC XY: 521 AN XY: 74496

African (AFR) AF: 0.00180 AC: 75 AN: 41570

American (AMR) AF: 0.0103 AC: 157 AN: 15310

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4832

European-Finnish (FIN) AF: 0.0107 AC: 114 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0103 AC: 702 AN: 68030

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00751 Hom.: 0

Bravo AF: 0.00690

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00807

EpiControl AF: 0.00765

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	7.5
DANN	Benign	0.63
PhyloP100		0.091
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: rs140831372; hg19: chr1-43890864;