rs143153487

Variant names:

• chr21-43774705-C-T
• rs143153487
• NM_000100.4:c.121G>A
• CSTB p.Val41Met

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000100.4(CSTB):​c.121G>A​(p.Val41Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,614,132 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (1 hom.)
• Consequence: CSTB NM_000100.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: -0.286
• Publications: 8 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017322361).
• BP6: Variant 21-43774705-C-T is Benign according to our data. Variant chr21-43774705-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195015.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000985 (150/152330) while in subpopulation SAS AF = 0.00228 (11/4826). AF 95% confidence interval is 0.00152. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000100.4. 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.121G>A	p.Val41Met	missense	Exon 2 of 3	NP_000091.1	Q76LA1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSTB	ENST00000291568.7	TSL:1 MANE Select	c.121G>A	p.Val41Met	missense	Exon 2 of 3	ENSP00000291568.6	P04080
	CSTB	ENST00000896953.1		c.109G>A	p.Val37Met	missense	Exon 2 of 3	ENSP00000567012.1
	CSTB	ENST00000937601.1		c.121G>A	p.Val41Met	missense	Exon 2 of 3	ENSP00000607660.1

Frequencies

GnomAD3 genomes AF: 0.000979 AC: 149 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00119 AC: 300 AN: 251478 AF XY: 0.00128

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.00175 AC: 2556 AN: 1461802 Hom.: 1 Cov.: 30 AF XY: 0.00176 AC XY: 1278 AN XY: 727208

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00167 AC: 144 AN: 86256

European-Finnish (FIN) AF: 0.00129 AC: 69 AN: 53400

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00200 AC: 2228 AN: 1111944

Other (OTH) AF: 0.00127 AC: 77 AN: 60394

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000953 AC XY: 71 AN XY: 74490

African (AFR) AF: 0.000168 AC: 7 AN: 41572

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00178 AC: 121 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00137 Hom.: 2

Bravo AF: 0.000861

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00190

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Unverricht-Lundborg syndrome (3)
-	1	1	not provided (2)
-	-	2	not specified (2)
-	-	1	CSTB-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	8.9
DANN	Benign	0.97
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.29
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.094
Sift	Benign	0.030	D
Sift4G	Uncertain	0.041	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.28
Mutation Taster		=99/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs143153487; hg19: chr21-45194586;