chr21-43774637-CTCCTGAGGCCCACACTCTA-TT

Variant names:

• chr21-43774637-CTCCTGAGGCCCACACTCTA-TT
• rs864309482
• NM_000100.4:c.168+2_168+21delTAGAGTGTGGGCCTCAGGAGinsAA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_000100.4(CSTB):​c.168+2_168+21delTAGAGTGTGGGCCTCAGGAGinsAA variant causes a splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CSTB NM_000100.4 splice_donor, splice_region, intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.256
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.34343433 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.8, offset of 25, new splice context is: ctgGTagga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSTB	NM_000100.4	c.168+2_168+21delTAGAGTGTGGGCCTCAGGAGinsAA		splice_donor_variant, splice_region_variant, intron_variant	Intron 2 of 2	ENST00000291568.7	NP_000091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSTB	ENST00000291568.7	c.168+2_168+21delTAGAGTGTGGGCCTCAGGAGinsAA		splice_donor_variant, splice_region_variant, intron_variant	Intron 2 of 2	1	NM_000100.4	ENSP00000291568.6
CSTB	ENST00000640406.1	c.170_189delTAGAGTGTGGGCCTCAGGAGinsAA	p.Val57_Gln62del	disruptive_inframe_deletion, synonymous_variant	Exon 2 of 2	2		ENSP00000492672.1
CSTB	ENST00000639959.1	c.34-326_34-307delTAGAGTGTGGGCCTCAGGAGinsAA		intron_variant	Intron 1 of 1	5		ENSP00000492123.1
CSTB	ENST00000675996.1	n.593+2_593+21delTAGAGTGTGGGCCTCAGGAGinsAA		splice_donor_variant, splice_region_variant, intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Unverricht-Lundborg syndrome Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.26
Mutation Taster		=7/93	disease causing (long InDel)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs864309482; hg19: chr21-45194518;