rs121909346

chr21-43774287-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000100.4(CSTB):c.212A>C(p.Gln71Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Q71Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CSTB NM_000100.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 0.0680

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a strand (size 10) in uniprot entity CYTB_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000100.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• PP5: Variant 21-43774287-T-G is Pathogenic according to our data. Variant chr21-43774287-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 8400.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-43774287-T-G is described in Lovd as [Pathogenic]. Variant chr21-43774287-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSTB	NM_000100.4	c.212A>C	p.Gln71Pro	missense_variant	3/3	ENST00000291568.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSTB	ENST00000291568.7	c.212A>C	p.Gln71Pro	missense_variant	3/3	1	NM_000100.4	P1
CSTB	ENST00000639959.1	c.80A>C	p.Gln27Pro	missense_variant	2/2	5
CSTB	ENST00000640406.1	c.*287A>C		3_prime_UTR_variant	2/2	2
CSTB	ENST00000675996.1	n.637A>C		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Unverricht-Lundborg syndrome Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2005	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	11
Dann	Uncertain	0.98
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	2.4e-10	A
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.028	D
Polyphen		0.75	P
Vest4		0.75
MutPred		0.43		Gain of disorder (P = 0.1331);
MVP		0.66
MPC		0.44
ClinPred		0.51	D
GERP RS		1.7
Varity_R		0.72
gMVP		0.79

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: rs121909346; hg19: chr21-45194168;