ENST00000675996.1:n.1157G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS1

The ENST00000675996.1(CSTB):n.1157G>A 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 0.000583 in 255,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00059 ( 0 hom. )

Consequence

CSTB
ENST00000675996.1 non_coding_transcript_exon

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.442

Publications

0 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000578 (88/152314) while in subpopulation NFE AF = 0.00121 (82/68024). AF 95% confidence interval is 0.000995. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSTB	NM_000100.4 link	c.*435G>A		downstream_gene_variant		ENST00000291568.7	NP_000091.1	P04080Q76LA1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CSTB	ENST00000675996.1 link	n.1157G>A	non_coding_transcript_exon_variant	Exon 3 of 3
CSTB	ENST00000640406.1 link	c.*807G>A	3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000492672.1	A0A1W2PS52
CSTB	ENST00000639959.1 link	c.*435G>A	3_prime_UTR_variant	Exon 2 of 2	5		ENSP00000492123.1	A0A1W2PQG6
CSTB	ENST00000291568.7 link	c.*435G>A	downstream_gene_variant		1	NM_000100.4	ENSP00000291568.6	P04080

Frequencies

GnomAD3 genomes

AF:

0.000578

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00121

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000590

AC:

AN:

103372

Hom.:

Cov.:

AF XY:

0.000508

AC XY:

AN XY:

55096

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

3100

American (AMR)

AF:

0.00

AC:

AN:

4278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2314

East Asian (EAS)

AF:

0.00

AC:

AN:

4588

South Asian (SAS)

AF:

0.00

AC:

AN:

18146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

348

European-Non Finnish (NFE)

AF:

0.000994

AC:

AN:

61344

Other (OTH)

AF:

0.00

AC:

AN:

4916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000578

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41574

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00121

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000688

Hom.:

Bravo

AF:

0.000620

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Unverricht-Lundborg syndrome

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

4.6

(source)

DANN

Benign

0.72

PhyloP100

0.44

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

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ENST00000675996.1:n.1157G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over