rs386833443

Variant names:

• chr21-43776204-C-A
• rs386833443
• NM_000100.4:c.66G>T

Your query was ambiguous. Multiple possible variants found:

• chr21-43776204-C-A
• chr21-43776204-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000100.4(CSTB):​c.66G>T​(p.Gln22His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,379,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q22Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: CSTB NM_000100.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56
• 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: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• keratolytic winter erythema

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSTB	NM_000100.4	c.66G>T	p.Gln22His	missense_variant, splice_region_variant	Exon 1 of 3	ENST00000291568.7	NP_000091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSTB	ENST00000291568.7	c.66G>T	p.Gln22His	missense_variant, splice_region_variant	Exon 1 of 3	1	NM_000100.4	ENSP00000291568.6
CSTB	ENST00000640406.1	c.66G>T	p.Gln22His	missense_variant, splice_region_variant	Exon 1 of 2	2		ENSP00000492672.1
CSTB	ENST00000639959.1	c.33G>T	p.Gln11His	missense_variant, splice_region_variant	Exon 1 of 2	5		ENSP00000492123.1
CSTB	ENST00000675996.1	n.127G>T		non_coding_transcript_exon_variant	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000435 AC: 6 AN: 1379530 Hom.: 0 Cov.: 31 AF XY: 0.00000441 AC XY: 3 AN XY: 680908

African (AFR) AF: 0.00 AC: 0 AN: 30062

American (AMR) AF: 0.00 AC: 0 AN: 35284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24904

East Asian (EAS) AF: 0.00 AC: 0 AN: 35064

South Asian (SAS) AF: 0.00 AC: 0 AN: 78194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5018

European-Non Finnish (NFE) AF: 0.00000372 AC: 4 AN: 1075084

Other (OTH) AF: 0.0000348 AC: 2 AN: 57502

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Pathogenic	35
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-1.1	T
PhyloP100		1.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Benign	0.037
Sift	Benign	0.034	D;.
Sift4G	Uncertain	0.045	D;.
Polyphen		0.011	B;.
Vest4		0.12
MutPred		0.38		Loss of disorder (P = 0.1872);Loss of disorder (P = 0.1872);
MVP		0.23
MPC		0.13
ClinPred		0.95	D
GERP RS		4.6
PromoterAI		-0.33	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.27
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		Position offset: -4
DS_DL_spliceai		0.34		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs386833443; hg19: chr21-45196085;