8-11845182-G-C

Variant names:

• chr8-11845182-G-C
• rs142780869
• NM_001908.5:c.963C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001908.5(CTSB):​c.963C>G​(p.Ile321Met) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I321I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CTSB NM_001908.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.340
• Publications: 0 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001908.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSB	NM_001908.5	MANE Select	c.963C>G	p.Ile321Met	missense	Exon 10 of 10	NP_001899.1	P07858
	CTSB	NM_001384714.1		c.963C>G	p.Ile321Met	missense	Exon 10 of 10	NP_001371643.1	A0A024R374
	CTSB	NM_001384723.1		c.963C>G	p.Ile321Met	missense	Exon 12 of 12	NP_001371652.1	P07858

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSB	ENST00000353047.11	TSL:1 MANE Select	c.963C>G	p.Ile321Met	missense	Exon 10 of 10	ENSP00000345672.5	P07858
	CTSB	ENST00000533455.6	TSL:1	c.963C>G	p.Ile321Met	missense	Exon 12 of 12	ENSP00000432244.1	P07858
	CTSB	ENST00000531551.5	TSL:1	n.*511C>G		non_coding_transcript_exon	Exon 10 of 10	ENSP00000436456.1	E9PCB3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251416 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.75	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		-0.34
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.85		Gain of disorder (P = 0.0678)
MVP		0.95
ClinPred		0.97	D
GERP RS		-9.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.87
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs142780869; hg19: chr8-11702691;