1-43389978-G-C

Variant names:

• chr1-43389978-G-C
• rs1570513799
• NM_001365999.1:c.10G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365999.1(SZT2):​c.10G>C​(p.Glu4Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. E4K) 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: 4.22

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2509784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SZT2	NM_001365999.1	c.10G>C	p.Glu4Gln	missense_variant	Exon 1 of 72	ENST00000634258.3	NP_001352928.1
MED8	NM_201542.5	c.-214C>G		upstream_gene_variant		ENST00000372457.9	NP_963836.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3	c.10G>C	p.Glu4Gln	missense_variant	Exon 1 of 72	5	NM_001365999.1	ENSP00000489255.1
MED8	ENST00000372457.9	c.-214C>G		upstream_gene_variant		2	NM_201542.5	ENSP00000361535.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.0011	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.043	.;T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.90	L;L;L
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.2	N;.;N
REVEL	Benign	0.12
Sift	Benign	0.052	T;.;D
Sift4G	Benign	0.24	T;D;D
Polyphen		0.99	D;.;.
Vest4		0.42
MutPred		0.16		Loss of glycosylation at S3 (P = 0.1856);Loss of glycosylation at S3 (P = 0.1856);Loss of glycosylation at S3 (P = 0.1856);
MVP		0.27
MPC		0.55
ClinPred		0.86	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs1570513799; hg19: chr1-43855649;