chr21-43774279-GGA-G

Variant names:

• chr21-43774279-GGA-G
• rs796943858
• NM_000100.4:c.218_219delTC

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1_Strong PS3 PP5_Very_Strong BS1_Supporting

The NM_000100.4(CSTB):​c.218_219delTC​(p.Leu73ProfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.000224 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000538020: in vitro functional studies have shown this variant leads to abnormal localization of the protein within the cell, similar to other pathogenic variants (Cipollini et al., 2008" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L73L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: CSTB NM_000100.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 5.03
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• Unverricht-Lundborg syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• autosomal recessive hypohidrotic ectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 15 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. Fraction of 0.266 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000538020: in vitro functional studies have shown this variant leads to abnormal localization of the protein within the cell, similar to other pathogenic variants (Cipollini et al., 2008; Alakurtti et al., 2005).; SCV002598543: The variant does not localize to the lysosomes which may contribute to misfunction (Alakurtti_2005).; SCV000566780: Published functional studies suggest that the variant does not localize to lysosomes as compared to unaffected controls (PMID: 15483648, 17920138); SCV000742064: Functional analysis demonstrated that levels of CSTB mRNA were significantly decreased in cells from patients heterozygous for the CSTB c.218_219delTC (p.L73Pfs*3) alteration compared to unaffected individuals (Lafrenière, 1997; Bespalova, 1997). When the L73Pfs*3 protein was expressed in vitro, the mutant protein had diffuse distribution in the cytoplasm and nucleus and did not colocalize with lysosomes (Alakurtti, 2005).; SCV000759812: Experimental studies have shown that this premature translational stop signal affects CSTB function (PMID: 9342192, 15483648, 17920138).
• PP5: Variant 21-43774279-GGA-G is Pathogenic according to our data. Variant chr21-43774279-GGA-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 55960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000241 (353/1461870) while in subpopulation NFE AF = 0.000308 (342/1112010). AF 95% confidence interval is 0.000281. There are 0 homozygotes in GnomAdExome4. There are 174 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000100.4. 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
	CSTB	NM_000100.4	MANE Select	c.218_219delTC	p.Leu73ProfsTer3	frameshift	Exon 3 of 3	NP_000091.1	Q76LA1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSTB	ENST00000291568.7	TSL:1 MANE Select	c.218_219delTC	p.Leu73ProfsTer3	frameshift	Exon 3 of 3	ENSP00000291568.6	P04080
	CSTB	ENST00000896953.1		c.206_207delTC	p.Leu69ProfsTer3	frameshift	Exon 3 of 3	ENSP00000567012.1
	CSTB	ENST00000937601.1		c.188_189delTC	p.Leu63ProfsTer3	frameshift	Exon 3 of 3	ENSP00000607660.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251470 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000241 AC: 353 AN: 1461870 Hom.: 0 AF XY: 0.000239 AC XY: 174 AN XY: 727234

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000308 AC: 342 AN: 1112010

Other (OTH) AF: 0.000149 AC: 9 AN: 60394

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74362

African (AFR) AF: 0.0000724 AC: 3 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Unverricht-Lundborg syndrome (6)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=10/190	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs796943858; hg19: chr21-45194160;