chr1-43420650-A-G

Variant names:

• chr1-43420650-A-G
• rs2782642
• NM_001365999.1:c.1262-99A>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.1262-99A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 1,169,220 control chromosomes in the GnomAD database, including 87,628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9829 hom., cov: 32)
  • Exomes 𝑓: 0.38 (77799 hom.)
• Consequence: SZT2 NM_001365999.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.510
• Publications: 12 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=-0.93).
• BP6: Variant 1-43420650-A-G is Benign according to our data. Variant chr1-43420650-A-G is described in ClinVar as Benign. ClinVar VariationId is 1256943.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SZT2	NM_001365999.1	MANE Select	c.1262-99A>G		intron	N/A	NP_001352928.1
	SZT2	NM_015284.4		c.1262-99A>G		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.1262-99A>G		intron	N/A	ENSP00000489255.1
	SZT2	ENST00000562955.2	TSL:5	c.1262-99A>G		intron	N/A	ENSP00000457168.1
	SZT2	ENST00000639852.1	TSL:5	n.928-99A>G		intron	N/A	ENSP00000492385.1

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53340 AN: 151886 Hom.: 9826 Cov.: 32

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.0992

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.405

GnomAD4 exome AF: 0.380 AC: 386267 AN: 1017216 Hom.: 77799 AF XY: 0.373 AC XY: 189984 AN XY: 509718

African (AFR) AF: 0.275 AC: 6765 AN: 24558

American (AMR) AF: 0.343 AC: 10582 AN: 30874

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 8172 AN: 19338

East Asian (EAS) AF: 0.122 AC: 4270 AN: 34942

South Asian (SAS) AF: 0.160 AC: 10395 AN: 64942

European-Finnish (FIN) AF: 0.389 AC: 12761 AN: 32776

Middle Eastern (MID) AF: 0.401 AC: 1295 AN: 3230

European-Non Finnish (NFE) AF: 0.414 AC: 315347 AN: 761222

Other (OTH) AF: 0.368 AC: 16680 AN: 45334

GnomAD4 genome AF: 0.351 AC: 53379 AN: 152004 Hom.: 9829 Cov.: 32 AF XY: 0.346 AC XY: 25715 AN XY: 74286

African (AFR) AF: 0.276 AC: 11429 AN: 41468

American (AMR) AF: 0.396 AC: 6047 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1471 AN: 3466

East Asian (EAS) AF: 0.0990 AC: 512 AN: 5172

South Asian (SAS) AF: 0.157 AC: 757 AN: 4824

European-Finnish (FIN) AF: 0.391 AC: 4122 AN: 10534

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.407 AC: 27675 AN: 67950

Other (OTH) AF: 0.403 AC: 847 AN: 2104

Alfa AF: 0.397 Hom.: 15761

Bravo AF: 0.352

Asia WGS AF: 0.152 AC: 528 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	8.1
DANN	Benign	0.66
PhyloP100		0.51
Mutation Taster		=100/0	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: rs2782642; hg19: chr1-43886321; COSMIC: COSV65173933; COSMIC: COSV65173933;