chr1-43441565-G-A

Variant names:

• chr1-43441565-G-A
• rs139486476
• NM_001365999.1:c.7573G>A

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.7573G>A​(p.Val2525Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,614,176 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2525G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0065 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (15 hom.)
• Consequence: SZT2 NM_001365999.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.31
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036810935).
• BP6: Variant 1-43441565-G-A is Benign according to our data. Variant chr1-43441565-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00652 (993/152290) while in subpopulation AFR AF = 0.0226 (941/41564). AF 95% confidence interval is 0.0214. There are 9 homozygotes in GnomAd4. There are 487 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.7573G>A	p.Val2525Ile	missense	Exon 54 of 72	NP_001352928.1
	SZT2	NM_015284.4		c.7402G>A	p.Val2468Ile	missense	Exon 53 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.7573G>A	p.Val2525Ile	missense	Exon 54 of 72	ENSP00000489255.1
	SZT2	ENST00000562955.2	TSL:5	c.7402G>A	p.Val2468Ile	missense	Exon 53 of 71	ENSP00000457168.1
	SZT2	ENST00000648058.1		n.4027G>A		non_coding_transcript_exon	Exon 22 of 40

Frequencies

GnomAD3 genomes AF: 0.00652 AC: 992 AN: 152172 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00576

GnomAD2 exomes AF: 0.00173 AC: 434 AN: 251412 AF XY: 0.00132

Gnomad AFR exome AF: 0.0238

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000634 AC: 927 AN: 1461886 Hom.: 15 Cov.: 52 AF XY: 0.000550 AC XY: 400 AN XY: 727248

African (AFR) AF: 0.0225 AC: 752 AN: 33478

American (AMR) AF: 0.000872 AC: 39 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1112010

Other (OTH) AF: 0.00151 AC: 91 AN: 60396

GnomAD4 genome AF: 0.00652 AC: 993 AN: 152290 Hom.: 9 Cov.: 32 AF XY: 0.00654 AC XY: 487 AN XY: 74466

African (AFR) AF: 0.0226 AC: 941 AN: 41564

American (AMR) AF: 0.00209 AC: 32 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68024

Other (OTH) AF: 0.00570 AC: 12 AN: 2106

Alfa AF: 0.00260 Hom.: 10

Bravo AF: 0.00753

ESP6500AA AF: 0.0268 AC: 118

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00218 AC: 265

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.1
DANN	Benign	0.87
DEOGEN2	Benign	0.064	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.36	N
Sift	Benign	1.0	T
Sift4G	Benign	0.068	T
Polyphen		0.0010	B
Vest4		0.14
MVP		0.072
MPC		0.30
ClinPred		0.0059	T
GERP RS		0.33
Varity_R		0.013
gMVP		0.27
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs139486476; hg19: chr1-43907236; COSMIC: COSV107469890; COSMIC: COSV107469890;