rs386833443

Variant names:

• chr21-43776204-C-T
• rs386833443
• NM_000100.4:c.66G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-43776204-C-T
• chr21-43776204-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000100.4(CSTB):​c.66G>A​(p.Gln22Gln) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CSTB NM_000100.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.56
• Publications: 11 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: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 21-43776204-C-T is Pathogenic according to our data. Variant chr21-43776204-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 55961.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000100.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSTB	NM_000100.4	MANE Select	c.66G>A	p.Gln22Gln	splice_region synonymous	Exon 1 of 3	NP_000091.1	Q76LA1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSTB	ENST00000291568.7	TSL:1 MANE Select	c.66G>A	p.Gln22Gln	splice_region synonymous	Exon 1 of 3	ENSP00000291568.6	P04080
	CSTB	ENST00000896953.1		c.66G>A	p.Gln22Gln	splice_region synonymous	Exon 1 of 3	ENSP00000567012.1
	CSTB	ENST00000937601.1		c.66G>A	p.Gln22Gln	splice_region synonymous	Exon 1 of 3	ENSP00000607660.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1379530 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 680908

African (AFR) AF: 0.00 AC: 0 AN: 30062

American (AMR) AF: 0.00 AC: 0 AN: 35284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24904

East Asian (EAS) AF: 0.00 AC: 0 AN: 35064

South Asian (SAS) AF: 0.00 AC: 0 AN: 78194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5018

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075084

Other (OTH) AF: 0.00 AC: 0 AN: 57502

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Unverricht-Lundborg syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	26
DANN	Benign	0.95
PhyloP100		1.6
PromoterAI		-0.28	Neutral
Mutation Taster		=30/70	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.47		Position offset: -4
DS_DL_spliceai		0.20		Position offset: 0

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

Other links and lift over

dbSNP: rs386833443; hg19: chr21-45196085;