21-43773877-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000640406.1(CSTB):c.*697A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0845 in 365,854 control chromosomes in the GnomAD database, including 1,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (461 hom., cov: 33)
  • Exomes 𝑓: 0.092 (1029 hom.)
• Consequence: CSTB ENST00000640406.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.08

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-43773877-T-C is Benign according to our data. Variant chr21-43773877-T-C is described in ClinVar as [Benign]. Clinvar id is 340116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSTB	ENST00000639959.1	c.*325A>G		3_prime_UTR_variant	2/2	5
CSTB	ENST00000640406.1	c.*697A>G		3_prime_UTR_variant	2/2	2
CSTB	ENST00000675996.1	n.1047A>G		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.0746 AC: 11356 AN: 152126 Hom.: 460 Cov.: 33

Gnomad AFR AF: 0.0653

Gnomad AMI AF: 0.0681

Gnomad AMR AF: 0.0455

Gnomad ASJ AF: 0.0669

Gnomad EAS AF: 0.0693

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.0715

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0835

Gnomad OTH AF: 0.0737

GnomAD4 exome AF: 0.0917 AC: 19578 AN: 213610 Hom.: 1029 Cov.: 0 AF XY: 0.0971 AC XY: 11367 AN XY: 117036

Gnomad4 AFR exome AF: 0.0628

Gnomad4 AMR exome AF: 0.0379

Gnomad4 ASJ exome AF: 0.0676

Gnomad4 EAS exome AF: 0.0638

Gnomad4 SAS exome AF: 0.146

Gnomad4 FIN exome AF: 0.0870

Gnomad4 NFE exome AF: 0.0842

Gnomad4 OTH exome AF: 0.0834

GnomAD4 genome AF: 0.0746 AC: 11350 AN: 152244 Hom.: 461 Cov.: 33 AF XY: 0.0730 AC XY: 5437 AN XY: 74436

Gnomad4 AFR AF: 0.0651

Gnomad4 AMR AF: 0.0453

Gnomad4 ASJ AF: 0.0669

Gnomad4 EAS AF: 0.0693

Gnomad4 SAS AF: 0.143

Gnomad4 FIN AF: 0.0715

Gnomad4 NFE AF: 0.0835

Gnomad4 OTH AF: 0.0729

Alfa AF: 0.0265 Hom.: 17

Bravo AF: 0.0702

Asia WGS AF: 0.104 AC: 359 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Unverricht-Lundborg syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.63
Dann	Benign	0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs28691645; hg19: chr21-45193758; COSMIC: COSV52366922; COSMIC: COSV52366922;