21-43773901-CG-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The ENST00000640406.1(CSTB):c.*672del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 386,120 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0046 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (1 hom.)
• Consequence: CSTB ENST00000640406.1 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.51

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 -10 ACMG points.

• BP6: Variant 21-43773901-CG-C is Benign according to our data. Variant chr21-43773901-CG-C is described in ClinVar as [Likely_benign]. Clinvar id is 1199992.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00459 (698/152184) while in subpopulation AFR AF= 0.0156 (648/41496). AF 95% confidence interval is 0.0146. There are 6 homozygotes in gnomad4. There are 320 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSTB	NM_000100.4			downstream_gene_variant		ENST00000291568.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSTB	ENST00000639959.1	c.*300del		3_prime_UTR_variant	2/2	5
CSTB	ENST00000640406.1	c.*672del		3_prime_UTR_variant	2/2	2
CSTB	ENST00000675996.1	n.1022del		non_coding_transcript_exon_variant	3/3
CSTB	ENST00000291568.7			downstream_gene_variant		1	NM_000100.4	P1

Frequencies

GnomAD3 genomes AF: 0.00458 AC: 696 AN: 152066 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00574

GnomAD4 exome AF: 0.000620 AC: 145 AN: 233936 Hom.: 1 Cov.: 2 AF XY: 0.000616 AC XY: 79 AN XY: 128206

Gnomad4 AFR exome AF: 0.0160

Gnomad4 AMR exome AF: 0.00176

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000481

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000673

Gnomad4 OTH exome AF: 0.000754

GnomAD4 genome AF: 0.00459 AC: 698 AN: 152184 Hom.: 6 Cov.: 33 AF XY: 0.00430 AC XY: 320 AN XY: 74428

Gnomad4 AFR AF: 0.0156

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00306 Hom.: 0

Bravo AF: 0.00476

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201363469; hg19: chr21-45193782;