rs561698107

Positions:

• chr1-43422871-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_001365999.1(SZT2):​c.2025G>A​(p.Pro675=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000455 in 1,585,562 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: SZT2 NM_001365999.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.715

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 1-43422871-G-A is Benign according to our data. Variant chr1-43422871-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 416964.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}. Variant chr1-43422871-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.715 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SZT2	NM_001365999.1	c.2025G>A	p.Pro675=	synonymous_variant	14/72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4	c.2025G>A	p.Pro675=	synonymous_variant	14/71		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3	c.2025G>A	p.Pro675=	synonymous_variant	14/72	5	NM_001365999.1	ENSP00000489255	P1
SZT2	ENST00000562955.2	c.2025G>A	p.Pro675=	synonymous_variant	14/71	5		ENSP00000457168
SZT2	ENST00000470139.1	c.756G>A	p.Pro252=	synonymous_variant, NMD_transcript_variant	5/18	2		ENSP00000492726

Frequencies

GnomAD3 genomes AF: 0.000317 AC: 48 AN: 151624 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000971

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000545

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000405 AC: 84 AN: 207294 Hom.: 0 AF XY: 0.000368 AC XY: 42 AN XY: 114280

Gnomad AFR exome AF: 0.000171

Gnomad AMR exome AF: 0.000123

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000123

Gnomad SAS exome AF: 0.0000369

Gnomad FIN exome AF: 0.000287

Gnomad NFE exome AF: 0.000677

Gnomad OTH exome AF: 0.00145

GnomAD4 exome AF: 0.000469 AC: 673 AN: 1433938 Hom.: 0 Cov.: 34 AF XY: 0.000423 AC XY: 301 AN XY: 712420

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.0000922

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.0000767

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.000242

Gnomad4 NFE exome AF: 0.000555

Gnomad4 OTH exome AF: 0.000585

GnomAD4 genome AF: 0.000317 AC: 48 AN: 151624 Hom.: 0 Cov.: 28 AF XY: 0.000324 AC XY: 24 AN XY: 74004

Gnomad4 AFR AF: 0.0000971

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000545

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000310

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	SZT2: PM2:Supporting, BP4 -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	13
DANN	Benign	0.77

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: rs561698107; hg19: chr1-43888542;