9-87728650-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001912.5(CTSL):​c.462A>C​(p.Lys154Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CTSL
NM_001912.5 missense

Scores

3
11
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.83
Variant links:
Genes affected
CTSL (HGNC:2537): (cathepsin L) The protein encoded by this gene is a lysosomal cysteine proteinase that plays a major role in intracellular protein catabolism. Its substrates include collagen and elastin, as well as alpha-1 protease inhibitor, a major controlling element of neutrophil elastase activity. The encoded protein has been implicated in several pathologic processes, including myofibril necrosis in myopathies and in myocardial ischemia, and in the renal tubular response to proteinuria. This protein, which is a member of the peptidase C1 family, is a dimer composed of disulfide-linked heavy and light chains, both produced from a single protein precursor. Additionally, this protein cleaves the S1 subunit of the SARS-CoV-2 spike protein, which is necessary for entry of the virus into the cell. [provided by RefSeq, Aug 2020]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CTSLNM_001912.5 linkc.462A>C p.Lys154Asn missense_variant 5/8 ENST00000343150.10 NP_001903.1 P07711-1A0A024R276

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CTSLENST00000343150.10 linkc.462A>C p.Lys154Asn missense_variant 5/81 NM_001912.5 ENSP00000345344.5 P07711-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 20, 2023The c.462A>C (p.K154N) alteration is located in exon 5 (coding exon 4) of the CTSL gene. This alteration results from a A to C substitution at nucleotide position 462, causing the lysine (K) at amino acid position 154 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.60
BayesDel_addAF
Benign
-0.040
T
BayesDel_noAF
Benign
-0.30
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.91
D;D;D
Eigen
Uncertain
0.28
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Uncertain
0.95
.;D;D
M_CAP
Benign
0.036
D
MetaRNN
Uncertain
0.57
D;D;D
MetaSVM
Uncertain
0.15
D
MutationAssessor
Uncertain
2.5
M;M;.
PrimateAI
Uncertain
0.59
T
PROVEAN
Pathogenic
-4.4
D;D;D
REVEL
Uncertain
0.48
Sift
Uncertain
0.011
D;D;D
Sift4G
Uncertain
0.021
D;D;D
Polyphen
0.85
P;P;.
Vest4
0.35
MutPred
0.68
Loss of ubiquitination at K154 (P = 0.0341);Loss of ubiquitination at K154 (P = 0.0341);Loss of ubiquitination at K154 (P = 0.0341);
MVP
0.92
MPC
0.49
ClinPred
0.99
D
GERP RS
0.70
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.69
gMVP
0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-90343565; API