21-43773919-GAA-G

Variant summary

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

The ENST00000640406.1(CSTB):c.*653_*654del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00434 in 423,580 control chromosomes in the GnomAD database, including 29 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0098 (26 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: CSTB ENST00000640406.1 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.362

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 21-43773919-GAA-G is Benign according to our data. Variant chr21-43773919-GAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 1209247.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00979 (1489/152104) while in subpopulation AFR AF= 0.033 (1368/41490). AF 95% confidence interval is 0.0315. There are 26 homozygotes in gnomad4. There are 724 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 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.*281_*282del		3_prime_UTR_variant	2/2	5
CSTB	ENST00000640406.1	c.*653_*654del		3_prime_UTR_variant	2/2	2
CSTB	ENST00000675996.1	n.1003_1004del		non_coding_transcript_exon_variant	3/3
CSTB	ENST00000291568.7			downstream_gene_variant		1	NM_000100.4	P1

Frequencies

GnomAD3 genomes AF: 0.00978 AC: 1486 AN: 151986 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.00129 AC: 351 AN: 271476 Hom.: 3 AF XY: 0.00108 AC XY: 158 AN XY: 146970

Gnomad4 AFR exome AF: 0.0299

Gnomad4 AMR exome AF: 0.00200

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000474

Gnomad4 FIN exome AF: 0.0000856

Gnomad4 NFE exome AF: 0.000245

Gnomad4 OTH exome AF: 0.00314

GnomAD4 genome AF: 0.00979 AC: 1489 AN: 152104 Hom.: 26 Cov.: 33 AF XY: 0.00974 AC XY: 724 AN XY: 74364

Gnomad4 AFR AF: 0.0330

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000280

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00790 Hom.: 1

Bravo AF: 0.0113

Asia WGS AF: 0.00231 AC: 8 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

Jul 17, 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: rs202136987; hg19: chr21-45193800;