chr21-43773919-GAA-G

Variant names:

• chr21-43773919-GAA-G
• rs202136987
• ENST00000675996.1:n.1003_1004delTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The ENST00000675996.1(CSTB):​n.1003_1004delTT variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00434 in 423,580 control chromosomes in the GnomAD database, including 29 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0098 (26 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: CSTB ENST00000675996.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.362
• Publications: 1 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 21-43773919-GAA-G is Benign according to our data. Variant chr21-43773919-GAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 1209247.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00979 (1489/152104) while in subpopulation AFR AF = 0.033 (1368/41490). AF 95% confidence interval is 0.0315. There are 26 homozygotes in GnomAd4. There are 724 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSTB	NM_000100.4	c.*281_*282delTT		downstream_gene_variant		ENST00000291568.7	NP_000091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSTB	ENST00000675996.1	n.1003_1004delTT		non_coding_transcript_exon_variant	Exon 3 of 3
CSTB	ENST00000640406.1	c.*653_*654delTT		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000492672.1
CSTB	ENST00000639959.1	c.*281_*282delTT		3_prime_UTR_variant	Exon 2 of 2	5		ENSP00000492123.1
CSTB	ENST00000291568.7	c.*281_*282delTT		downstream_gene_variant		1	NM_000100.4	ENSP00000291568.6

Frequencies

GnomAD3 genomes AF: 0.00978 AC: 1486 AN: 151986 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.00129 AC: 351 AN: 271476 Hom.: 3 AF XY: 0.00108 AC XY: 158 AN XY: 146970

African (AFR) AF: 0.0299 AC: 234 AN: 7828

American (AMR) AF: 0.00200 AC: 26 AN: 13020

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7196

East Asian (EAS) AF: 0.00 AC: 0 AN: 13624

South Asian (SAS) AF: 0.0000474 AC: 2 AN: 42176

European-Finnish (FIN) AF: 0.0000856 AC: 1 AN: 11688

Middle Eastern (MID) AF: 0.00152 AC: 4 AN: 2626

European-Non Finnish (NFE) AF: 0.000245 AC: 39 AN: 158982

Other (OTH) AF: 0.00314 AC: 45 AN: 14336

GnomAD4 genome AF: 0.00979 AC: 1489 AN: 152104 Hom.: 26 Cov.: 33 AF XY: 0.00974 AC XY: 724 AN XY: 74364

African (AFR) AF: 0.0330 AC: 1368 AN: 41490

American (AMR) AF: 0.00536 AC: 82 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

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

European-Non Finnish (NFE) AF: 0.000280 AC: 19 AN: 67968

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00790 Hom.: 1

Bravo AF: 0.0113

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 17, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs202136987; hg19: chr21-45193800;