rs143153487

chr21-43774705-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6 BS1 BS2

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. 13/20 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

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 195015.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=2, Benign=2}. Variant chr21-43774705-C-T is described in Lovd as [Benign]. Variant chr21-43774705-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSTB	NM_000100.4	c.121G>A	p.Val41Met	missense_variant	2/3	ENST00000291568.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSTB	ENST00000291568.7	c.121G>A	p.Val41Met	missense_variant	2/3	1	NM_000100.4	P1
CSTB	ENST00000640406.1	c.121G>A	p.Val41Met	missense_variant	2/2	2
CSTB	ENST00000639959.1	c.36-375G>A		intron_variant		5
CSTB	ENST00000675996.1	n.546G>A		non_coding_transcript_exon_variant	2/3

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

GnomAD3 exomes AF: 0.00119 AC: 300 AN: 251478 Hom.: 2 AF XY: 0.00128 AC XY: 174 AN XY: 135914

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 SAS exome AF: 0.00186

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

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00167

Gnomad4 FIN exome AF: 0.00129

Gnomad4 NFE exome AF: 0.00200

Gnomad4 OTH exome AF: 0.00127

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

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00178

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00146 Hom.: 1

Bravo AF: 0.000861

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00119 AC: 144

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Unverricht-Lundborg syndrome Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 29, 2016	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2021	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 15, 2020	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CSTB-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 25, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Progressive myoclonic epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.0	N;.
REVEL	Benign	0.094
Sift	Benign	0.030	D;.
Sift4G	Uncertain	0.041	D;.
Polyphen		0.89	P;.
Vest4		0.37
MVP		0.048
MPC		0.29
ClinPred		0.020	T
GERP RS		-6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs143153487; hg19: chr21-45194586;