Genetic Variant SZT2:p.Pro6Leu (chr1-43389985-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001365999.1(SZT2):c.17C>T(p.Pro6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000161 in 1,241,702 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P6R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

SZT2
NM_001365999.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.36

Publications

0 publications found

Variant links:

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 links:

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]

MED8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2669578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SZT2	NM_001365999.1 link	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 72	ENST00000634258.3	NP_001352928.1
MED8	NM_201542.5 link	c.-221G>A		upstream_gene_variant		ENST00000372457.9	NP_963836.2	Q96G25-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3 link	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 72	5	NM_001365999.1	ENSP00000489255.1		Q5T011-1
MED8	ENST00000372457.9 link	c.-221G>A		upstream_gene_variant		2	NM_201542.5	ENSP00000361535.4		Q96G25-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000161

AC:

AN:

1241702

Hom.:

Cov.:

AF XY:

0.00000166

AC XY:

AN XY:

601476

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24874

American (AMR)

AF:

0.00

AC:

AN:

13746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17764

East Asian (EAS)

AF:

0.0000344

AC:

AN:

29096

South Asian (SAS)

AF:

0.00

AC:

AN:

60350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30786

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4726

European-Non Finnish (NFE)

AF:

9.91e-7

AC:

AN:

1008890

Other (OTH)

AF:

0.00

AC:

AN:

51470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.068

.;T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.77

T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.6

L;L;L

PhyloP100

3.4

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.6

D;.;N

REVEL

Benign

0.23

Sift

Benign

0.12

T;.;T

Sift4G

Uncertain

0.059

T;D;D

Polyphen

1.0

D;.;.

Vest4

0.45

MutPred

0.40

Loss of glycosylation at P6 (P = 0.0218);Loss of glycosylation at P6 (P = 0.0218);Loss of glycosylation at P6 (P = 0.0218);

MVP

0.34

MPC

0.54

ClinPred

0.95

GERP RS

4.3

PromoterAI

-0.065

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.19

Mutation Taster

=80/20

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over