NM_001908.5:c.1001A>C

Variant names:

• chr8-11845144-T-G
• rs117613666
• NM_001908.5:c.1001A>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001908.5(CTSB):​c.1001A>C​(p.Gln334Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,613,564 control chromosomes in the GnomAD database, including 39 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 0.0024 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (34 hom.)
• Consequence: CTSB NM_001908.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.07

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007766694).
• BP6: Variant 8-11845144-T-G is Benign according to our data. Variant chr8-11845144-T-G is described in ClinVar as [Benign]. Clinvar id is 728614.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0024 (366/152320) while in subpopulation EAS AF= 0.0301 (156/5190). AF 95% confidence interval is 0.0262. There are 5 homozygotes in gnomad4. There are 255 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 366 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSB	NM_001908.5	c.1001A>C	p.Gln334Pro	missense_variant	Exon 10 of 10	ENST00000353047.11	NP_001899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSB	ENST00000353047.11	c.1001A>C	p.Gln334Pro	missense_variant	Exon 10 of 10	1	NM_001908.5	ENSP00000345672.5

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 365 AN: 152202 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0298

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00383 AC: 962 AN: 251404 Hom.: 15 AF XY: 0.00380 AC XY: 516 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0327

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.000501

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00157 AC: 2301 AN: 1461244 Hom.: 34 Cov.: 30 AF XY: 0.00156 AC XY: 1131 AN XY: 726994

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0322

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.000131

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00240 AC: 366 AN: 152320 Hom.: 5 Cov.: 33 AF XY: 0.00342 AC XY: 255 AN XY: 74492

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0301

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0149

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00158 Hom.: 3

Bravo AF: 0.00151

ExAC AF: 0.00367 AC: 446

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;T;T;T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.71	.;.;.;.;.;.;T
MetaRNN	Benign	0.0078	T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.5	L;L;L;L;L;L;L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N
REVEL	Benign	0.29
Sift	Uncertain	0.013	D;D;D;D;D;D;D
Sift4G	Benign	0.072	T;T;T;T;T;T;T
Polyphen		0.20	B;B;B;B;B;B;B
Vest4		0.32
MVP		0.68
ClinPred		0.027	T
GERP RS		4.6
Varity_R		0.78
gMVP		0.84

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: rs117613666; hg19: chr8-11702653; COSMIC: COSV100565848; COSMIC: COSV100565848;