rs536069557

Variant names:

• chr21-43773883-C-T
• rs536069557
• ENST00000640406.1:c.*691G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The ENST00000640406.1(CSTB):​c.*691G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000457 in 369,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (0 hom.)
• Consequence: CSTB ENST00000640406.1 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.933
• 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, Labcorp Genetics (formerly Invitae), Orphanet
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000513 (78/152112) while in subpopulation AMR AF = 0.000916 (14/15290). AF 95% confidence interval is 0.000677. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000640406.1. 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.*319G>A		downstream_gene	N/A	NP_000091.1	Q76LA1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSTB	ENST00000640406.1	TSL:2	c.*691G>A		3_prime_UTR	Exon 2 of 2	ENSP00000492672.1	A0A1W2PS52
	CSTB	ENST00000639959.1	TSL:5	c.*319G>A		3_prime_UTR	Exon 2 of 2	ENSP00000492123.1	A0A1W2PQG6
	CSTB	ENST00000675996.1		n.1041G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 151994 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

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: 0.000853

Gnomad OTH AF: 0.000959

GnomAD4 exome AF: 0.000418 AC: 91 AN: 217644 Hom.: 0 Cov.: 0 AF XY: 0.000411 AC XY: 49 AN XY: 119276

African (AFR) AF: 0.00 AC: 0 AN: 5950

American (AMR) AF: 0.000810 AC: 9 AN: 11112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5134

East Asian (EAS) AF: 0.00 AC: 0 AN: 9300

South Asian (SAS) AF: 0.00 AC: 0 AN: 40792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2158

European-Non Finnish (NFE) AF: 0.000658 AC: 81 AN: 123100

Other (OTH) AF: 0.0000920 AC: 1 AN: 10866

GnomAD4 genome AF: 0.000513 AC: 78 AN: 152112 Hom.: 0 Cov.: 33 AF XY: 0.000457 AC XY: 34 AN XY: 74364

African (AFR) AF: 0.0000965 AC: 4 AN: 41456

American (AMR) AF: 0.000916 AC: 14 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000853 AC: 58 AN: 68000

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.000521

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.52
DANN	Benign	0.49
PhyloP100		-0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs536069557; hg19: chr21-45193764;