21-43774128-A-G

Position:

• chr21-43774128-A-G

Variant summary

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

The NM_000100.4(CSTB):​c.*74T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,603,536 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (63 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (57 hom.)
• Consequence: CSTB NM_000100.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.131

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 21-43774128-A-G is Benign according to our data. Variant chr21-43774128-A-G is described in ClinVar as [Benign]. Clinvar id is 340119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSTB	NM_000100.4	c.*74T>C		3_prime_UTR_variant	3/3	ENST00000291568.7	NP_000091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSTB	ENST00000291568	c.*74T>C		3_prime_UTR_variant	3/3	1	NM_000100.4	ENSP00000291568.6

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2354 AN: 152178 Hom.: 60 Cov.: 33

Gnomad AFR AF: 0.0525

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.00170 AC: 2469 AN: 1451240 Hom.: 57 Cov.: 28 AF XY: 0.00148 AC XY: 1068 AN XY: 722682

Gnomad4 AFR exome AF: 0.0567

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000934

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000154

Gnomad4 OTH exome AF: 0.00371

GnomAD4 genome AF: 0.0155 AC: 2368 AN: 152296 Hom.: 63 Cov.: 33 AF XY: 0.0151 AC XY: 1125 AN XY: 74478

Gnomad4 AFR AF: 0.0527

Gnomad4 AMR AF: 0.00778

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00501 Hom.: 18

Bravo AF: 0.0179

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2018	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.9
DANN	Benign	0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs6385; hg19: chr21-45194009;