chr21-43773847-G-C

Variant names:

• chr21-43773847-G-C
• rs143062585
• ENST00000675996.1:n.1077C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000675996.1(CSTB):​n.1077C>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 0.00764 in 351,074 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0081 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (9 hom.)
• Consequence: CSTB ENST00000675996.1 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.579
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 21-43773847-G-C is Benign according to our data. Variant chr21-43773847-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 340115.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00813 (1239/152354) while in subpopulation AFR AF = 0.0121 (503/41584). AF 95% confidence interval is 0.0112. There are 7 homozygotes in GnomAd4. There are 636 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSTB	NM_000100.4	c.*355C>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.1077C>G		non_coding_transcript_exon_variant	Exon 3 of 3
CSTB	ENST00000640406.1	c.*727C>G		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000492672.1
CSTB	ENST00000639959.1	c.*355C>G		3_prime_UTR_variant	Exon 2 of 2	5		ENSP00000492123.1
CSTB	ENST00000291568.7	c.*355C>G		downstream_gene_variant		1	NM_000100.4	ENSP00000291568.6

Frequencies

GnomAD3 genomes AF: 0.00805 AC: 1225 AN: 152236 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00706

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.00952

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00692

Gnomad OTH AF: 0.0115

GnomAD4 exome AF: 0.00726 AC: 1442 AN: 198720 Hom.: 9 Cov.: 0 AF XY: 0.00758 AC XY: 824 AN XY: 108764

African (AFR) AF: 0.0127 AC: 69 AN: 5452

American (AMR) AF: 0.00502 AC: 49 AN: 9752

Ashkenazi Jewish (ASJ) AF: 0.00859 AC: 40 AN: 4656

East Asian (EAS) AF: 0.00122 AC: 10 AN: 8168

South Asian (SAS) AF: 0.00932 AC: 360 AN: 38640

European-Finnish (FIN) AF: 0.00454 AC: 39 AN: 8586

Middle Eastern (MID) AF: 0.00955 AC: 12 AN: 1256

European-Non Finnish (NFE) AF: 0.00710 AC: 799 AN: 112504

Other (OTH) AF: 0.00659 AC: 64 AN: 9706

GnomAD4 genome AF: 0.00813 AC: 1239 AN: 152354 Hom.: 7 Cov.: 33 AF XY: 0.00854 AC XY: 636 AN XY: 74498

African (AFR) AF: 0.0121 AC: 503 AN: 41584

American (AMR) AF: 0.00706 AC: 108 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3472

East Asian (EAS) AF: 0.00231 AC: 12 AN: 5192

South Asian (SAS) AF: 0.00973 AC: 47 AN: 4828

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00691 AC: 470 AN: 68034

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.00807

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CSTB: BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Unverricht-Lundborg syndrome Uncertain:1

Jan 13, 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	-0.85
CADD	Benign	6.5
DANN	Benign	0.70
PhyloP100		0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism

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: rs143062585; hg19: chr21-45193728;