8-11869308-A-G

Variant names:

• chr8-11869308-A-G
• rs1296023
• ENST00000534382.6:c.-457T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000534382.6(CTSB):​c.-457T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 149,306 control chromosomes in the GnomAD database, including 7,936 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (7929 hom., cov: 27)
  • Exomes 𝑓: 0.35 (7 hom.)
• Consequence: CTSB ENST00000534382.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.339
• Publications: 18 publications found

Genes affected

CTSB (HGNC:2527): (cathepsin B) This gene encodes a member of the C1 family of peptidases. Alternative splicing of this gene results in multiple transcript variants. At least one of these variants encodes a preproprotein that is proteolytically processed to generate multiple protein products. These products include the cathepsin B light and heavy chains, which can dimerize to form the double chain form of the enzyme. This enzyme is a lysosomal cysteine protease with both endopeptidase and exopeptidase activity that may play a role in protein turnover. It is also known as amyloid precursor protein secretase and is involved in the proteolytic processing of amyloid precursor protein (APP). Incomplete proteolytic processing of APP has been suggested to be a causative factor in Alzheimer's disease, the most common cause of dementia. Overexpression of the encoded protein has been associated with esophageal adenocarcinoma and other tumors. Both Cathepsin B and Cathepsin L are involved in the cleavage of the spike protein from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) upon its entry to the human host cell. Multiple pseudogenes of this gene have been identified. [provided by RefSeq, Sep 2020]

CTSB Gene-Disease associations (from GenCC):

• keratolytic winter erythema

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000534382.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSB	ENST00000534382.6	TSL:4	c.-457T>C		5_prime_UTR	Exon 1 of 10	ENSP00000435260.2
	CTSB	ENST00000677671.1		c.-412T>C		5_prime_UTR	Exon 1 of 10	ENSP00000503578.1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 48500 AN: 149110 Hom.: 7930 Cov.: 27

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.484

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.281

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.312

GnomAD4 exome AF: 0.347 AC: 34 AN: 98 Hom.: 7 Cov.: 0 AF XY: 0.368 AC XY: 28 AN XY: 76

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.350 AC: 28 AN: 80

Other (OTH) AF: 0.667 AC: 4 AN: 6

GnomAD4 genome AF: 0.325 AC: 48532 AN: 149208 Hom.: 7929 Cov.: 27 AF XY: 0.327 AC XY: 23764 AN XY: 72686

African (AFR) AF: 0.318 AC: 12836 AN: 40414

American (AMR) AF: 0.305 AC: 4578 AN: 15022

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 748 AN: 3458

East Asian (EAS) AF: 0.485 AC: 2413 AN: 4976

South Asian (SAS) AF: 0.366 AC: 1729 AN: 4722

European-Finnish (FIN) AF: 0.356 AC: 3556 AN: 9998

Middle Eastern (MID) AF: 0.275 AC: 77 AN: 280

European-Non Finnish (NFE) AF: 0.320 AC: 21569 AN: 67376

Other (OTH) AF: 0.314 AC: 648 AN: 2066

Alfa AF: 0.317 Hom.: 27800

Bravo AF: 0.318

Asia WGS AF: 0.413 AC: 1436 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.5
DANN	Benign	0.56
PhyloP100		0.34
PromoterAI		0.010	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1296023; hg19: chr8-11726817;