chr21-43773847-G-C

Variant names:

• chr21-43773847-G-C
• rs143062585
• ENST00000640406.1:c.*727C>G

Variant summary

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

The ENST00000640406.1(CSTB):​c.*727C>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 0.00764 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 ENST00000640406.1 3_prime_UTR
• 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: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• 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 VariationId is 340115.
• 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

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.*355C>G		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.*727C>G		3_prime_UTR	Exon 2 of 2	ENSP00000492672.1	A0A1W2PS52
	CSTB	ENST00000639959.1	TSL:5	c.*355C>G		3_prime_UTR	Exon 2 of 2	ENSP00000492123.1	A0A1W2PQG6
	CSTB	ENST00000675996.1		n.1077C>G		non_coding_transcript_exon	Exon 3 of 3

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Unverricht-Lundborg syndrome (1)

Computational scores

Source: dbNSFP v4.9

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;