ENST00000675996.1:n.1047A>G

Variant names:

• chr21-43773877-T-C
• rs28691645
• ENST00000675996.1:n.1047A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000675996.1(CSTB):​n.1047A>G variant causes a non coding transcript exon 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 ENST00000675996.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.08
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Unverricht-Lundborg syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• keratolytic winter erythema

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• autosomal recessive hypohidrotic ectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CSTB	NM_000100.4	c.*325A>G		downstream_gene_variant		ENST00000291568.7	NP_000091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSTB	ENST00000675996.1	n.1047A>G		non_coding_transcript_exon_variant	Exon 3 of 3
CSTB	ENST00000640406.1	c.*697A>G		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000492672.1
CSTB	ENST00000639959.1	c.*325A>G		3_prime_UTR_variant	Exon 2 of 2	5		ENSP00000492123.1
CSTB	ENST00000291568.7	c.*325A>G		downstream_gene_variant		1	NM_000100.4	ENSP00000291568.6

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

African (AFR) AF: 0.0628 AC: 367 AN: 5842

American (AMR) AF: 0.0379 AC: 412 AN: 10874

Ashkenazi Jewish (ASJ) AF: 0.0676 AC: 339 AN: 5018

East Asian (EAS) AF: 0.0638 AC: 577 AN: 9044

South Asian (SAS) AF: 0.146 AC: 5913 AN: 40412

European-Finnish (FIN) AF: 0.0870 AC: 794 AN: 9128

Middle Eastern (MID) AF: 0.0655 AC: 135 AN: 2060

European-Non Finnish (NFE) AF: 0.0842 AC: 10156 AN: 120616

Other (OTH) AF: 0.0834 AC: 885 AN: 10616

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

African (AFR) AF: 0.0651 AC: 2705 AN: 41524

American (AMR) AF: 0.0453 AC: 694 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0669 AC: 232 AN: 3470

East Asian (EAS) AF: 0.0693 AC: 359 AN: 5182

South Asian (SAS) AF: 0.143 AC: 691 AN: 4824

European-Finnish (FIN) AF: 0.0715 AC: 759 AN: 10612

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0835 AC: 5677 AN: 68012

Other (OTH) AF: 0.0729 AC: 154 AN: 2112

Alfa AF: 0.0558 Hom.: 93

Bravo AF: 0.0702

Asia WGS AF: 0.104 AC: 359 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Unverricht-Lundborg syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.90
CADD	Benign	0.63
DANN	Benign	0.33
PhyloP100		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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