rs74315442

Positions:

chr21-43774297-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_000100.4(CSTB):c.202C>T(p.Arg68Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

CSTB
NM_000100.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 0.935

Variant links:

Genes affected

CSTB (HGNC:2482): (cystatin B) The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and kininogens. This gene encodes a stefin that functions as an intracellular thiol protease inhibitor. The protein is able to form a dimer stabilized by noncovalent forces, inhibiting papain and cathepsins l, h and b. The protein is thought to play a role in protecting against the proteases leaking from lysosomes. Evidence indicates that mutations in this gene are responsible for the primary defects in patients with progressive myoclonic epilepsy (EPM1). One type of mutation responsible for EPM1 is the expansion in the promoter region of this gene of a CCCCGCCCCGCG repeat from 2-3 copies to 30-78 copies. [provided by RefSeq, Jul 2016]

CSTB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 21-43774297-G-A is Pathogenic according to our data. Variant chr21-43774297-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43774297-G-A is described in Lovd as [Pathogenic]. Variant chr21-43774297-G-A is described in Lovd as [Likely_pathogenic]. Variant chr21-43774297-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSTB	NM_000100.4 linkuse as main transcript	c.202C>T	p.Arg68Ter	stop_gained	3/3	ENST00000291568.7	NP_000091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CSTB	ENST00000291568.7 linkuse as main transcript	c.202C>T	p.Arg68Ter	stop_gained	3/3	1	NM_000100.4	ENSP00000291568	P1
CSTB	ENST00000639959.1 linkuse as main transcript	c.70C>T	p.Arg24Ter	stop_gained	2/2	5		ENSP00000492123
CSTB	ENST00000640406.1 linkuse as main transcript	c.*277C>T		3_prime_UTR_variant	2/2	2		ENSP00000492672
CSTB	ENST00000675996.1 linkuse as main transcript	n.627C>T		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251462

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000499

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000612

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000462

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Unverricht-Lundborg syndrome

Pathogenic:3Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Jan 25, 2024	The CSTB c.202C>T (p.Arg68Ter) variant has been reported in over 10 patients with Unverricht-Lundborg syndrome and is reported to segregate with disease in six individuals in three families (Koskenkorva P et al., PMID: 21757863; Lafreniere RG et al., PMID: 9054946; Mancini GM et al., PMID: 26843564, Pennacchio LA et al., PMID: 8596935). Of those individuals, two siblings were homozygous for the variant (Mancini GM et al., PMID: 26843564) and seven were compound heterozygous for the variant and a pathogenic repeat expansion confirmed in trans (Koskenkorva P et al., PMID: 21757863). This variant leads to a premature termination codon; however, because this occurs in the last exon, this is not predicted to lead to nonsense mediated decay. It does disrupt the last 31 amino acids of the CSTB protein. Functional studies show protein aggregation in the perinuclear region and reduced cell viability compared to wild type, indicating that this variant impacts protein function (Ceru S et al., PMID: 20078424; Rabzelj S et al., PMID: 16155205). This variant is only observed on 13 out of 282,868 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant has been reported in the ClinVar database as a germline pathogenic variant by five submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	The c.202C>T (p.Arg68Ter) variant has been reported in at least five studies in which it is found in a total of 11 Unverricht-Lundborg disease patients, including two affected siblings in a homozygous state, seven patients in a compound heterozygous state (including two sibling pairs), and in two patient alleles where zygosity was not specified (Pennacchio et al. 1996; LafreniÃ¨re et al. 1997; de Haan et al. 2004; Koskenkorva et al. 2010; Mancini et al. 2016). The p.Arg68Ter variant was absent from 377 controls but is reported at a frequency of 0.00006 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Functional analyses demonstrated that the variant resulted in reduced cell viability by 26% compared to wild-type in transfected CHO-K1 cells (Ceru et al. 2010). Additionally, the p.Arg68Ter variant protein did not localize to the nucleus. The variant produced an unfolded protein leading to protein aggregation which resulted in perinuclear aggregates that were more pronounced than wild type (Rabzelj et al. 2005; Ceru et al. 2010; Polajnar et al. 2012). Based on the evidence and the potential impact of stop-gained variants, the p.Arg68Ter variant is classified as pathogenic for Unverricht-Lundborg disease. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2005	- -

Childhood epilepsy with centrotemporal spikes

Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 17, 2022

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with progressive myoclonic epilepsy. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant leads to the formation of protein aggregates (PMID: 17920138, 20078424) -

Dyskinesia;C0013421:Dystonic disorder;C0036857:Intellectual disability, severe;C0241816:Global brain atrophy;C1837397:Severe global developmental delay;C1850456:Progressive microcephaly;C1854301:Motor delay;C1861866:Aplasia/Hypoplasia of the corpus callosum

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Progressive myoclonic epilepsy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 08, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CSTB protein in which other variant(s) (p.Leu73Profs*3) have been determined to be pathogenic (PMID: 9054946, 9342192, 15483648, 17920138). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this premature translational stop signal affects CSTB function (PMID: 15483648). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 8396). This premature translational stop signal has been observed in individual(s) with progressive myoclonus epilepsy (PMID: 8596935, 26843564). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs74315442, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Arg68*) in the CSTB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the CSTB protein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Benign

0.96

Eigen

Benign

0.13

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.58

MutationTaster

Benign

1.0

Vest4

0.89

GERP RS

-0.43

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over