1-43389973-C-T

Variant names:

• chr1-43389973-C-T
• rs1301582193
• NM_001365999.1:c.5C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001365999.1(SZT2):​c.5C>T​(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 1,253,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: SZT2 NM_001365999.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.36
• Publications: 1 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]

MED8 (HGNC:19971): (mediator complex subunit 8) This gene encodes a protein component of the mediator complex, which aids in transcriptional activation through interaction with RNA polymerase II and gene-specific transcription factors. The encoded protein may also function in ubiquitin ligation and protein degradation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2013]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39518386).

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.5C>T	p.Ala2Val	missense	Exon 1 of 72	NP_001352928.1	Q5T011-1
	SZT2	NM_015284.4		c.5C>T	p.Ala2Val	missense	Exon 1 of 71	NP_056099.3	Q5T011-5
	MED8	NM_201542.5	MANE Select	c.-209G>A		upstream_gene	N/A	NP_963836.2	Q96G25-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SZT2	ENST00000634258.3	TSL:5 MANE Select	c.5C>T	p.Ala2Val	missense	Exon 1 of 72	ENSP00000489255.1	Q5T011-1
	SZT2	ENST00000372450.8	TSL:1	c.5C>T	p.Ala2Val	missense	Exon 1 of 5	ENSP00000361528.4	Q5T011-7
	SZT2	ENST00000357658.4	TSL:1	n.23C>T		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000207 AC: 1 AN: 48276 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000384

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000263 AC: 33 AN: 1253546 Hom.: 0 Cov.: 34 AF XY: 0.0000279 AC XY: 17 AN XY: 608338

African (AFR) AF: 0.00 AC: 0 AN: 25442

American (AMR) AF: 0.00 AC: 0 AN: 15362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17964

East Asian (EAS) AF: 0.00 AC: 0 AN: 29834

South Asian (SAS) AF: 0.00 AC: 0 AN: 62052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4916

European-Non Finnish (NFE) AF: 0.0000325 AC: 33 AN: 1014294

Other (OTH) AF: 0.00 AC: 0 AN: 52014

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.90	L
PhyloP100		3.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.21
Sift	Benign	0.097	T
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.23		Gain of stability (P = 0.0144)
MVP		0.36
MPC		0.55
ClinPred		0.87	D
GERP RS		4.3
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.23
Mutation Taster		=80/20	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: rs1301582193; hg19: chr1-43855644;