rs74315443

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate

The NM_000100.4(CSTB):c.10G>T(p.Gly4Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000218 in 1,376,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G4R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

CSTB
NM_000100.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.44

Publications

12 publications found

Variant links:

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

CSTB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-43776260-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 8397.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

PP5

Variant 21-43776260-C-A is Pathogenic according to our data. Variant chr21-43776260-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 431700.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSTB	NM_000100.4 link	c.10G>T	p.Gly4Trp	missense_variant	Exon 1 of 3	ENST00000291568.7	NP_000091.1	P04080Q76LA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CSTB	ENST00000291568.7 link	c.10G>T	p.Gly4Trp	missense_variant	Exon 1 of 3	1	NM_000100.4	ENSP00000291568.6	P04080
CSTB	ENST00000640406.1 link	c.10G>T	p.Gly4Trp	missense_variant	Exon 1 of 2	2		ENSP00000492672.1	A0A1W2PS52
CSTB	ENST00000675996.1 link	n.71G>T		non_coding_transcript_exon_variant	Exon 1 of 3
CSTB	ENST00000639959.1 link	c.-24G>T		upstream_gene_variant		5		ENSP00000492123.1	A0A1W2PQG6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

125582

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000436

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000218

AC:

AN:

1376180

Hom.:

Cov.:

AF XY:

0.00000295

AC XY:

AN XY:

678816

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29374

American (AMR)

AF:

0.00

AC:

AN:

34584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24612

East Asian (EAS)

AF:

0.00

AC:

AN:

34314

South Asian (SAS)

AF:

0.0000258

AC:

AN:

77396

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40998

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5498

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1072152

Other (OTH)

AF:

0.0000175

AC:

AN:

57252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Unverricht-Lundborg syndrome

Pathogenic:1

TIDEX, University of British Columbia

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.89

D;.

Eigen

Benign

0.072

Eigen_PC

Benign

-0.099

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.76

T;T

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.99

PhyloP100

3.4

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-6.0

D;.

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.69

MutPred

0.84

Gain of catalytic residue at G4 (P = 0.0099);Gain of catalytic residue at G4 (P = 0.0099);

MVP

0.86

MPC

0.33

ClinPred

0.99

GERP RS

1.7

PromoterAI

0.096

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.91

gMVP

0.80

Mutation Taster

=36/64

disease causing (ClinVar)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over