chr1-43441689-G-T

Variant names:

• chr1-43441689-G-T
• rs1553153691
• NM_001365999.1:c.7613G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001365999.1(SZT2):​c.7613G>T​(p.Cys2538Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C2538Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SZT2 NM_001365999.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.09
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

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.7613G>T	p.Cys2538Phe	missense	Exon 55 of 72	NP_001352928.1
	SZT2	NM_015284.4		c.7442G>T	p.Cys2481Phe	missense	Exon 54 of 71	NP_056099.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SZT2	ENST00000634258.3	TSL:5 MANE Select	c.7613G>T	p.Cys2538Phe	missense	Exon 55 of 72	ENSP00000489255.1
	SZT2	ENST00000562955.2	TSL:5	c.7442G>T	p.Cys2481Phe	missense	Exon 54 of 71	ENSP00000457168.1
	SZT2	ENST00000648058.1		n.4067G>T		non_coding_transcript_exon	Exon 23 of 40

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 53

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.0	D
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.57		Loss of catalytic residue at S2483 (P = 0.0611)
MVP		0.40
MPC		1.2
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.75
gMVP		0.79
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1553153691; hg19: chr1-43907360;