21-43774109-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000100.4(CSTB):c.*93A>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 0.0144 in 1,562,300 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., cov: 33)
  • Exomes 𝑓: 0.015 (186 hom.)
• Consequence: CSTB NM_000100.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.47

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 21-43774109-T-C is Benign according to our data. Variant chr21-43774109-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 897702.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-43774109-T-C is described in Lovd as [Likely_benign]. Variant chr21-43774109-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0124 (1889/152298) while in subpopulation NFE AF= 0.0181 (1232/68016). AF 95% confidence interval is 0.0173. There are 22 homozygotes in gnomad4. There are 852 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSTB	NM_000100.4	c.*93A>G		3_prime_UTR_variant	3/3	ENST00000291568.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSTB	ENST00000291568.7	c.*93A>G		3_prime_UTR_variant	3/3	1	NM_000100.4	P1
CSTB	ENST00000639959.1	c.*93A>G		3_prime_UTR_variant	2/2	5
CSTB	ENST00000640406.1	c.*465A>G		3_prime_UTR_variant	2/2	2
CSTB	ENST00000675996.1	n.815A>G		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1890 AN: 152180 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0167

GnomAD4 exome AF: 0.0146 AC: 20585 AN: 1410002 Hom.: 186 Cov.: 25 AF XY: 0.0146 AC XY: 10282 AN XY: 704566

Gnomad4 AFR exome AF: 0.00198

Gnomad4 AMR exome AF: 0.00905

Gnomad4 ASJ exome AF: 0.0330

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.00835

Gnomad4 FIN exome AF: 0.00607

Gnomad4 NFE exome AF: 0.0163

Gnomad4 OTH exome AF: 0.0136

GnomAD4 genome AF: 0.0124 AC: 1889 AN: 152298 Hom.: 22 Cov.: 33 AF XY: 0.0114 AC XY: 852 AN XY: 74472

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.0130

Gnomad4 ASJ AF: 0.0357

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.00499

Gnomad4 NFE AF: 0.0181

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00402 Hom.: 1

Bravo AF: 0.0129

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Unverricht-Lundborg syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.090
Dann	Benign	0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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: rs9446; hg19: chr21-45193990;