21-43774109-T-C

Variant names:

• chr21-43774109-T-C
• rs9446
• NM_000100.4:c.*93A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000100.4(CSTB):​c.*93A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,562,300 control chromosomes in the GnomAD database, including 208 homozygotes. 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 0.012 (22 hom., cov: 33)
  • Exomes 𝑓: 0.015 (186 hom.)
• Consequence: CSTB NM_000100.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.47
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0124 (1889/152298) while in subpopulation NFE AF = 0.0181 (1232/68016). AF 95% confidence interval is 0.0173. There are 22 homozygotes in GnomAd4. There are 852 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSTB	NM_000100.4	c.*93A>G		3_prime_UTR_variant	Exon 3 of 3	ENST00000291568.7	NP_000091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSTB	ENST00000291568.7	c.*93A>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_000100.4	ENSP00000291568.6
CSTB	ENST00000675996.1	n.815A>G		non_coding_transcript_exon_variant	Exon 3 of 3
CSTB	ENST00000640406.1	c.*465A>G		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000492672.1
CSTB	ENST00000639959.1	c.*93A>G		3_prime_UTR_variant	Exon 2 of 2	5		ENSP00000492123.1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1890 AN: 152180 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0167

GnomAD4 exome AF: 0.0146 AC: 20585 AN: 1410002 Hom.: 186 Cov.: 25 AF XY: 0.0146 AC XY: 10282 AN XY: 704566

African (AFR) AF: 0.00198 AC: 64 AN: 32372

American (AMR) AF: 0.00905 AC: 402 AN: 44416

Ashkenazi Jewish (ASJ) AF: 0.0330 AC: 851 AN: 25752

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39412

South Asian (SAS) AF: 0.00835 AC: 706 AN: 84592

European-Finnish (FIN) AF: 0.00607 AC: 323 AN: 53212

Middle Eastern (MID) AF: 0.0188 AC: 107 AN: 5690

European-Non Finnish (NFE) AF: 0.0163 AC: 17331 AN: 1065906

Other (OTH) AF: 0.0136 AC: 799 AN: 58650

GnomAD4 genome AF: 0.0124 AC: 1889 AN: 152298 Hom.: 22 Cov.: 33 AF XY: 0.0114 AC XY: 852 AN XY: 74472

African (AFR) AF: 0.00308 AC: 128 AN: 41564

American (AMR) AF: 0.0130 AC: 199 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 124 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4824

European-Finnish (FIN) AF: 0.00499 AC: 53 AN: 10614

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.0181 AC: 1232 AN: 68016

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.00402 Hom.: 1

Bravo AF: 0.0129

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Unverricht-Lundborg syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.090
DANN	Benign	0.44
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
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: rs9446; hg19: chr21-45193990;