Genetic Variant SZT2:p.Pro2712Pro (chr1-43442603-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001365999.1(SZT2):c.8136C>T(p.Pro2712Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,604,230 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2712P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 18 hom. )

Consequence

SZT2
NM_001365999.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.39

Publications

6 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 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 18
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Illumina, G2P, Ambry Genetics
genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SZT2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001365999.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 1-43442603-C-T is Benign according to our data. Variant chr1-43442603-C-T is described in ClinVar as Benign. ClinVar VariationId is 241038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.39 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0015 (229/152294) while in subpopulation EAS AF = 0.0398 (206/5180). AF 95% confidence interval is 0.0353. There are 9 homozygotes in GnomAd4. There are 137 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR,AD gene

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.8136C>T	p.Pro2712Pro	synonymous	Exon 58 of 72	NP_001352928.1	Q5T011-1
	SZT2	NM_015284.4		c.7965C>T	p.Pro2655Pro	synonymous	Exon 57 of 71	NP_056099.3	Q5T011-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SZT2	ENST00000634258.3	TSL:5 MANE Select	c.8136C>T	p.Pro2712Pro	synonymous	Exon 58 of 72	ENSP00000489255.1	Q5T011-1
SZT2	ENST00000562955.2	TSL:5	c.7965C>T	p.Pro2655Pro	synonymous	Exon 57 of 71	ENSP00000457168.1	Q5T011-5
SZT2	ENST00000648058.1		n.4590C>T		non_coding_transcript_exon	Exon 26 of 40

Frequencies

GnomAD3 genomes

AF:

0.00151

AC:

230

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0399

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00367

AC:

906

AN:

246552

AF XY:

0.00351

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.000147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0464

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000807

Gnomad OTH exome

AF:

0.00100

GnomAD4 exome

AF:

0.00103

AC:

1490

AN:

1451936

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

740

AN XY:

720628

show subpopulations

African (AFR)

AF:

0.0000600

AC:

AN:

33316

American (AMR)

AF:

0.0000904

AC:

AN:

44256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25758

East Asian (EAS)

AF:

0.0315

AC:

1244

AN:

39470

South Asian (SAS)

AF:

0.000959

AC:

AN:

85482

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52534

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.0000308

AC:

AN:

1105438

Other (OTH)

AF:

0.00197

AC:

118

AN:

59954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

171

256

342

427

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00150

AC:

229

AN:

152294

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

137

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41562

American (AMR)

AF:

0.000131

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0398

AC:

206

AN:

5180

South Asian (SAS)

AF:

0.00124

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68024

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000164

Hom.:

Bravo

AF:

0.00213

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Developmental and epileptic encephalopathy, 18 (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.49

(source)

DANN

Benign

0.55

PhyloP100

-2.4

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over