8-11845196-C-T

Position:

• chr8-11845196-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001908.5(CTSB):​c.949G>A​(p.Asp317Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000644 in 1,613,798 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (6 hom.)
• Consequence: CTSB NM_001908.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.91

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0092069805).
• BP6: Variant 8-11845196-C-T is Benign according to our data. Variant chr8-11845196-C-T is described in ClinVar as [Benign]. Clinvar id is 1559085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 113 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSB	NM_001908.5	c.949G>A	p.Asp317Asn	missense_variant	10/10	ENST00000353047.11	NP_001899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSB	ENST00000353047.11	c.949G>A	p.Asp317Asn	missense_variant	10/10	1	NM_001908.5	ENSP00000345672.5

Frequencies

GnomAD3 genomes AF: 0.000743 AC: 113 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0142

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00207 AC: 521 AN: 251408 Hom.: 5 AF XY: 0.00185 AC XY: 252 AN XY: 135868

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.0238

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000634 AC: 927 AN: 1461494 Hom.: 6 Cov.: 30 AF XY: 0.000656 AC XY: 477 AN XY: 727078

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.000842

Gnomad4 EAS exome AF: 0.0148

Gnomad4 SAS exome AF: 0.000951

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.0000756

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.000886 AC XY: 66 AN XY: 74466

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0143

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000906 Hom.: 0

Bravo AF: 0.00111

ExAC AF: 0.00200 AC: 243

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 15, 2022	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D;D;D;D;D;D;D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	.;.;.;.;.;.;D
MetaRNN	Benign	0.0092	T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.83	N;N;N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.1	D;D;D;D;D;D;D
REVEL	Benign	0.27
Sift	Benign	0.50	T;T;T;T;T;T;T
Sift4G	Benign	0.57	T;T;T;T;T;T;T
Polyphen		0.16	B;B;B;B;B;B;B
Vest4		0.19
MVP		0.65
ClinPred		0.061	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.58
gMVP		0.58

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

LitVar

Other links and lift over

dbSNP: rs79487342; hg19: chr8-11702705;