21-43774297-G-C

Variant names:

• chr21-43774297-G-C
• NM_000100.4:c.202C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000100.4(CSTB):​c.202C>G​(p.Arg68Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CSTB NM_000100.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.935

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Cystatin-B (size 97) in uniprot entity CYTB_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_000100.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSTB	NM_000100.4	c.202C>G	p.Arg68Gly	missense_variant	Exon 3 of 3	ENST00000291568.7	NP_000091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSTB	ENST00000291568.7	c.202C>G	p.Arg68Gly	missense_variant	Exon 3 of 3	1	NM_000100.4	ENSP00000291568.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0064	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.11
Sift	Benign	0.039	D
Sift4G	Uncertain	0.032	D
Polyphen		0.039	B
Vest4		0.72
MutPred		0.63		Gain of catalytic residue at V69 (P = 0.0227);
MVP		0.14
MPC		0.20
ClinPred		0.93	D
GERP RS		-0.43
Varity_R		0.85
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-45194178;