1-43390008-C-T

Variant names:

• chr1-43390008-C-T
• rs1648080112
• NM_001365999.1:c.27+13C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001365999.1(SZT2):​c.27+13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SZT2 NM_001365999.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.105
• 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]

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-43390008-C-T is Benign according to our data. Variant chr1-43390008-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2739365.Status of the report is criteria_provided_single_submitter, 1 stars.

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.27+13C>T		intron	N/A	NP_001352928.1	Q5T011-1
	SZT2	NM_015284.4		c.27+13C>T		intron	N/A	NP_056099.3	Q5T011-5
	MED8	NM_201542.5	MANE Select	c.-244G>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.27+13C>T		intron	N/A	ENSP00000489255.1	Q5T011-1
	SZT2	ENST00000372450.8	TSL:1	c.27+13C>T		intron	N/A	ENSP00000361528.4	Q5T011-7
	SZT2	ENST00000357658.4	TSL:1	n.45+13C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.11e-7 AC: 1 AN: 1232404 Hom.: 0 Cov.: 34 AF XY: 0.00000168 AC XY: 1 AN XY: 595780

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24424

American (AMR) AF: 0.0000777 AC: 1 AN: 12876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17562

East Asian (EAS) AF: 0.00 AC: 0 AN: 28706

South Asian (SAS) AF: 0.00 AC: 0 AN: 58542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4252

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1005070

Other (OTH) AF: 0.00 AC: 0 AN: 51062

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	14
DANN	Benign	0.95
PhyloP100		0.10
PromoterAI		0.052	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1648080112; hg19: chr1-43855679;